|
Inhibition of human recombinant JAK1 by TR-FRET assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.
Year : 2010
Volume : 20
Issue : 24
First Page : 7454
Last Page : 7457
Authors : Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D'Andrea A.
Abstract : Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.
|
Inhibition of human recombinant JAK2 by TR-FRET assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.
Year : 2010
Volume : 20
Issue : 24
First Page : 7454
Last Page : 7457
Authors : Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D'Andrea A.
Abstract : Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.
|
Inhibition of human recombinant JAK3 by TR-FRET assay
|
Homo sapiens
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.
Year : 2010
Volume : 20
Issue : 24
First Page : 7454
Last Page : 7457
Authors : Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D'Andrea A.
Abstract : Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.
|
Inhibition of human recombinant TYK2 by TR-FRET assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.
Year : 2010
Volume : 20
Issue : 24
First Page : 7454
Last Page : 7457
Authors : Malerich JP, Lam JS, Hart B, Fine RM, Klebansky B, Tanga MJ, D'Andrea A.
Abstract : Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.
|
Binding constant for DCAMKL3 kinase domain
|
None
|
260.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MYLK kinase domain
|
None
|
360.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DYRK1A kinase domain
|
None
|
910.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for GRK7 kinase domain
|
None
|
540.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TAK1 kinase domain
|
None
|
730.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK2A kinase domain
|
None
|
46.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK2G kinase domain
|
None
|
100.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for ANKK1 kinase domain
|
None
|
390.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for LRRK2 kinase domain
|
None
|
290.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for LRRK2(G2019S) kinase domain
|
None
|
90.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for LTK kinase domain
|
None
|
440.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TRKC kinase domain
|
None
|
330.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK2D kinase domain
|
None
|
90.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for STK16 kinase domain
|
None
|
490.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for JAK3(JH1domain-catalytic) kinase domain
|
None
|
2.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RSK3(Kin.Dom.2-C-terminal) kinase domain
|
None
|
150.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DCAMKL2 kinase domain
|
None
|
760.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for BMPR2 kinase domain
|
None
|
930.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK2B kinase domain
|
None
|
310.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DAPK3 kinase domain
|
None
|
89.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for IRAK1 kinase domain
|
None
|
290.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for JAK1(JH1domain-catalytic) kinase domain
|
None
|
3.4
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MAP3K3 kinase domain
|
None
|
150.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MEK3 kinase domain
|
None
|
470.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for GRK1 kinase domain
|
None
|
730.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RSK1(Kin.Dom.2-C-terminal) kinase domain
|
None
|
120.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TTK kinase domain
|
None
|
480.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TYK2(JH1domain-catalytic) kinase domain
|
None
|
0.9
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for ULK1 kinase domain
|
None
|
300.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK1 kinase domain
|
None
|
470.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RPS6KA4(Kin.Dom.2-C-terminal) kinase domain
|
None
|
340.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CLK2 kinase domain
|
None
|
460.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PLK3 kinase domain
|
None
|
710.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DCAMKL1 kinase domain
|
None
|
68.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RPS6KA5(Kin.Dom.2-C-terminal) kinase domain
|
None
|
140.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for ROCK2 kinase domain
|
None
|
52.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DAPK1 kinase domain
|
None
|
72.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for JAK2(JH1domain-catalytic) kinase domain
|
None
|
0.036
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PLK1 kinase domain
|
None
|
130.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for GAK kinase domain
|
None
|
99.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PRKCE kinase domain
|
None
|
530.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for ROCK1 kinase domain
|
None
|
60.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TRKB kinase domain
|
None
|
360.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PRKG2 kinase domain
|
None
|
690.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MAP3K2 kinase domain
|
None
|
41.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for PLK4 kinase domain
|
None
|
200.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for DAPK2 kinase domain
|
None
|
97.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RSK4(Kin.Dom.2-C-terminal) kinase domain
|
None
|
150.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for ULK2 kinase domain
|
None
|
190.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for AAK1 kinase domain
|
None
|
120.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MAST1 kinase domain
|
None
|
520.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TAOK2 kinase domain
|
None
|
310.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for TAOK3 kinase domain
|
None
|
590.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MARK2 kinase domain
|
None
|
660.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for MKNK2 kinase domain
|
None
|
200.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for BIKE kinase domain
|
None
|
210.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for CAMK1D kinase domain
|
None
|
120.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RET kinase domain
|
None
|
720.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RET(M918T) kinase domain
|
None
|
630.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RET(V804L) kinase domain
|
None
|
280.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for RET(V804M) kinase domain
|
None
|
190.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for YSK4 kinase domain
|
None
|
270.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Binding constant for SNARK kinase domain
|
None
|
320.0
nM
|
|
Journal : Nat. Biotechnol.
Title : Comprehensive analysis of kinase inhibitor selectivity.
Year : 2011
Volume : 29
Issue : 11
First Page : 1046
Last Page : 1051
Authors : Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.
Abstract : We tested the interaction of 72 kinase inhibitors with 442 kinases covering >80% of the human catalytic protein kinome. Our data show that, as a class, type II inhibitors are more selective than type I inhibitors, but that there are important exceptions to this trend. The data further illustrate that selective inhibitors have been developed against the majority of kinases targeted by the compounds tested. Analysis of the interaction patterns reveals a class of 'group-selective' inhibitors broadly active against a single subfamily of kinases, but selective outside that subfamily. The data set suggests compounds to use as tools to study kinases for which no dedicated inhibitors exist. It also provides a foundation for further exploring kinase inhibitor biology and toxicity, as well as for studying the structural basis of the observed interaction patterns. Our findings will help to realize the direct enabling potential of genomics for drug development and basic research about cellular signaling.
|
Inhibition of human JAK3 kinase domain expressed in Sf21 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
428.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
Year : 2012
Volume : 55
Issue : 12
First Page : 5901
Last Page : 5921
Authors : Kulagowski JJ, Blair W, Bull RJ, Chang C, Deshmukh G, Dyke HJ, Eigenbrot C, Ghilardi N, Gibbons P, Harrison TK, Hewitt PR, Liimatta M, Hurley CA, Johnson A, Johnson T, Kenny JR, Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M.
Abstract : A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
|
Inhibition of human JAK2 kinase domain expressed in Sf21 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
2.8
nM
|
|
Journal : J. Med. Chem.
Title : Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
Year : 2012
Volume : 55
Issue : 12
First Page : 5901
Last Page : 5921
Authors : Kulagowski JJ, Blair W, Bull RJ, Chang C, Deshmukh G, Dyke HJ, Eigenbrot C, Ghilardi N, Gibbons P, Harrison TK, Hewitt PR, Liimatta M, Hurley CA, Johnson A, Johnson T, Kenny JR, Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M.
Abstract : A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
|
Inhibition of human JAK1 kinase domain expressed in Sf21 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
Year : 2012
Volume : 55
Issue : 12
First Page : 5901
Last Page : 5921
Authors : Kulagowski JJ, Blair W, Bull RJ, Chang C, Deshmukh G, Dyke HJ, Eigenbrot C, Ghilardi N, Gibbons P, Harrison TK, Hewitt PR, Liimatta M, Hurley CA, Johnson A, Johnson T, Kenny JR, Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M.
Abstract : A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
|
Inhibition of human TYK2 kinase domain expressed in Sf21 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors.
Year : 2012
Volume : 55
Issue : 12
First Page : 5901
Last Page : 5921
Authors : Kulagowski JJ, Blair W, Bull RJ, Chang C, Deshmukh G, Dyke HJ, Eigenbrot C, Ghilardi N, Gibbons P, Harrison TK, Hewitt PR, Liimatta M, Hurley CA, Johnson A, Johnson T, Kenny JR, Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M.
Abstract : A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
|
Inhibition of JAK1 kinase domain using N-terminal 5-carboxyfluorescein-tagged Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr as substrate after 30 mins
|
None
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of JAK2 kinase domain using N-terminal 5-carboxyfluorescein-tagged Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr as substrate after 30 mins
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of JAK3 kinase domain using N-terminal 5-carboxyfluorescein-tagged Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg as substrate after 30 mins
|
None
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of TYK2 kinase domain using N-terminal 5-carboxyfluorescein-tagged Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr as substrate after 30 mins
|
None
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of JAK1 in human TF1 cells assessed as inhibition of IL6-induced STAT3 phosphorylation incubated for 20 mins prior to IL6-induction measured after 30 to 45 mins
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of JAK2 in human TF1 cells assessed as inhibition of EPO-induced STAT5 phosphorylation incubated for 20 mins prior to EPO-induction measured after 30 to 45 mins
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Year : 2012
Volume : 55
Issue : 13
First Page : 6176
Last Page : 6193
Authors : Zak M, Mendonca R, Balazs M, Barrett K, Bergeron P, Blair WS, Chang C, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ghilardi N, Gibbons P, Gradl S, Hamman C, Hanan EJ, Harstad E, Hewitt PR, Hurley CA, Jin T, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Kulagowski JJ, Labadie S, Liao J, Liimatta M, Lin Z, Lupardus PJ, Maxey RJ, Murray JM, Pulk R, Rodriguez M, Savage S, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Xiao L, Xiao Y.
Abstract : Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
|
Inhibition of purified TYK2 incubated for 30 mins
|
None
|
0.55
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of purified JAK3 incubated for 30 mins
|
None
|
3.22
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of purified JAK1 incubated for 30 mins
|
None
|
0.09
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of purified JAK2 incubated for 30 mins
|
None
|
0.24
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of JAK2 V617F mutant in human SET2 cells assessed as reduction in STAT5 phosphorylation
|
Homo sapiens
|
1.84
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of JAK2 in human TF1 cells assessed as reduction in STAT5 phosphorylation incubated for 30 mins in presence of human recombinant EPO
|
Homo sapiens
|
6.85
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.
Year : 2012
Volume : 55
Issue : 22
First Page : 10090
Last Page : 10107
Authors : Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP.
Abstract : The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.
|
Inhibition of JAK2/1 in human T cells expressing CD3 assessed as inhibition of IFNgamma-stimulated STAT1 phosphorylation
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of JAK2 in human monocytes expressing CD14 assessed as inhibition of GM-CSF-stimulated STAT5a phosphorylation
|
Homo sapiens
|
26.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of JAK3/1 in human T cells expressing CD3 assessed as inhibition of IL2-stimulated STAT5a phosphorylation
|
Homo sapiens
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of JAK1 (unknown origin) using [33gammaP]ATP and Biotin-KAIETDKEYYTVKD as substrate incubated for 10 mins prior to substrate addition measured after 1 hr by filtration assay
|
Homo sapiens
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of JAK2 (unknown origin) using [33gammaP]ATP and Biotin-KAIETDKEYYTVKD as substrate incubated for 10 mins prior to substrate addition measured after 30 mins by filtration assay
|
Homo sapiens
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of JAK3 (unknown origin) using [33gammaP]ATP and Biotin-KAIETDKEYYTVKD as substrate incubated for 10 mins prior to substrate addition measured after 30 mins by filtration assay
|
Homo sapiens
|
10.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome.
Year : 2013
Volume : 23
Issue : 9
First Page : 2793
Last Page : 2800
Authors : Lynch SM, DeVicente J, Hermann JC, Jaime-Figueroa S, Jin S, Kuglstatter A, Li H, Lovey A, Menke J, Niu L, Patel V, Roy D, Soth M, Steiner S, Tivitmahaisoon P, Vu MD, Yee C.
Abstract : Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family.
|
Inhibition of human TYK2 (873-1187) expressed in baculovirus-infected Sf9 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of human JAK3 (781-1124) expressed in baculovirus-infected Sf9 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of human JAK2 (828-1132) expressed in baculovirus-infected Sf9 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of human JAK1 (837-1142) expressed in baculovirus-infected Sf9 cells using EQEDEPEGDYFEWLE as substrate after 1 hr by HTRF assay
|
Homo sapiens
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of JAK2 (unknown origin) assessed as inhibition of STAT5 phosphorylation by cell-based assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of JAK1 (unknown origin) assessed as inhibition of STAT3 phosphorylation by cell-based assay
|
Homo sapiens
|
24.0
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of TYK2 (unknown origin) assessed as inhibition of STAT4 phosphorylation by cell-based assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of TYK2 (unknown origin)
|
Homo sapiens
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.
Year : 2013
Volume : 56
Issue : 11
First Page : 4521
Last Page : 4536
Authors : Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, DeVoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S.
Abstract : Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.
|
Inhibition of TYK2 (unknown origin)
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.
Year : 2014
Volume : 24
Issue : 4
First Page : 1116
Last Page : 1121
Authors : McDonnell ME, Bian H, Wrobel J, Smith GR, Liang S, Ma H, Reitz AB.
Abstract : We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
14.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.
Year : 2014
Volume : 24
Issue : 4
First Page : 1116
Last Page : 1121
Authors : McDonnell ME, Bian H, Wrobel J, Smith GR, Liang S, Ma H, Reitz AB.
Abstract : We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
0.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.
Year : 2014
Volume : 24
Issue : 4
First Page : 1116
Last Page : 1121
Authors : McDonnell ME, Bian H, Wrobel J, Smith GR, Liang S, Ma H, Reitz AB.
Abstract : We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.
Year : 2014
Volume : 24
Issue : 4
First Page : 1116
Last Page : 1121
Authors : McDonnell ME, Bian H, Wrobel J, Smith GR, Liang S, Ma H, Reitz AB.
Abstract : We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
|
Cytotoxicity against mouse BAF3 cells expressing JAK2 V617F mutant after 48 hrs by CellTiterGlo assay
|
Mus musculus
|
126.0
nM
|
|
Journal : MedChemComm
Title : Inhibitors of Stat5 protein signalling
Year : 2012
Volume : 3
Issue : 1
First Page : 22
Last Page : 27
Authors : Cumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT
|
Inhibition of JAK-mediated STAT5 phosphorylation in HEL cells by Western blotting analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : MedChemComm
Title : Inhibitors of Stat5 protein signalling
Year : 2012
Volume : 3
Issue : 1
First Page : 22
Last Page : 27
Authors : Cumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
3.3
nM
|
|
Journal : MedChemComm
Title : Inhibitors of Stat5 protein signalling
Year : 2012
Volume : 3
Issue : 1
First Page : 22
Last Page : 27
Authors : Cumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
6.4
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
8.8
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
487.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of TYK2 (unknown origin)
|
Homo sapiens
|
30.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK1/JAK2/TYK2 in human whole blood assessed as inhibition of IL-6-induced STAT-1 phosphorylation preincubated for 45 mins followed by IL-6 addition measured after 15 mins by FACS analysis
|
Homo sapiens
|
298.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK1/TYK2 in human whole blood assessed as inhibition of IFN-alpha-induced STAT-3 phosphorylation preincubated for 45 mins followed by IFN-alpha addition measured after 15 mins by FACS analysis
|
Homo sapiens
|
194.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK2/TYK2 in human whole blood assessed as inhibition of IL-23-induced STAT-3 phosphorylation preincubated for 45 mins followed by IL-23 addition measured after 15 mins by FACS analysis
|
Homo sapiens
|
818.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of JAK2 homodimer in human CD34+ cells spiked into human whole blood assessed as inhibition of EPO-induced STAT-5 phosphorylation preincubated for 45 mins followed by EPO addition measured after 15 mins by FACS analysis
|
Homo sapiens
|
677.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases.
Year : 2014
Volume : 57
Issue : 12
First Page : 5023
Last Page : 5038
Authors : Clark JD, Flanagan ME, Telliez JB.
Abstract : The Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play an essential role in the signaling of numerous cytokines that have been implicated in the pathogenesis of inflammatory diseases. As a consequence, the JAKs have received significant attention in recent years from the pharmaceutical and biotechnology industries as therapeutic targets. Here, we provide a review of the JAK pathways, the structure, function, and activation of the JAK enzymes followed by a detailed look at the JAK inhibitors currently in the clinic or approved for these indications. Finally, a perspective is provided on what the past decade of research with JAK inhibitors for inflammatory indications has taught along with thoughts on what the future may hold in terms of addressing the opportunities and challenges that remain.
|
Inhibition of human recombinant JAK1
|
Homo sapiens
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.
Year : 2014
Volume : 57
Issue : 22
First Page : 9323
Last Page : 9342
Authors : Menet CJ, Fletcher SR, Van Lommen G, Geney R, Blanc J, Smits K, Jouannigot N, Deprez P, van der Aar EM, Clement-Lacroix P, Lepescheux L, Galien R, Vayssiere B, Nelles L, Christophe T, Brys R, Uhring M, Ciesielski F, Van Rompaey L.
Abstract : Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).
|
Inhibition of human recombinant JAK2
|
Homo sapiens
|
0.2
nM
|
|
Journal : J. Med. Chem.
Title : Triazolopyridines as selective JAK1 inhibitors: from hit identification to GLPG0634.
Year : 2014
Volume : 57
Issue : 22
First Page : 9323
Last Page : 9342
Authors : Menet CJ, Fletcher SR, Van Lommen G, Geney R, Blanc J, Smits K, Jouannigot N, Deprez P, van der Aar EM, Clement-Lacroix P, Lepescheux L, Galien R, Vayssiere B, Nelles L, Christophe T, Brys R, Uhring M, Ciesielski F, Van Rompaey L.
Abstract : Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
0.43
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
0.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of TYK2 (unknown origin)
|
Homo sapiens
|
0.72
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of JAK1 in human PBMC cells assessed as inhibition of IL-6-induced MCP1 secretion
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of JAK2 in human CD34+ cells assessed as inhibition of EPO-mediated cell proliferation
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition IL-7-indcued STAT5 phosphorylation in human PBMC cells by flow cytometry
|
Homo sapiens
|
448.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure-based design and development of (benz)imidazole pyridones as JAK1-selective kinase inhibitors.
Year : 2016
Volume : 26
Issue : 7
First Page : 1803
Last Page : 1808
Authors : Simov V, Deshmukh SV, Dinsmore CJ, Elwood F, Fernandez RB, Garcia Y, Gibeau C, Gunaydin H, Jung J, Katz JD, Kraybill B, Lapointe B, Patel SB, Siu T, Su H, Young JR.
Abstract : The mammalian Janus Kinases (JAK1, JAK2, JAK3 and TYK2) are intracellular, non-receptor tyrosine kinases whose activities have been associated in the literature and the clinic with a variety of hyperproliferative diseases and immunological disorders. At the onset of the program, it was hypothesized that a JAK1 selective compound over JAK2 could lead to an improved therapeutic index relative to marketed non-selective JAK inhibitors by avoiding the clinical AEs, such as anemia, presumably associated with JAK2 inhibition. During the course of the JAK1 program, a number of diverse chemical scaffolds were identified from both uHTS campaigns and de novo scaffold design. As part of this effort, a (benz)imidazole scaffold evolved via a scaffold-hopping exercise from a mature chemical series. Concurrent crystallography-driven exploration of the ribose pocket and the solvent front led to analogs with optimized kinome and JAK1 selectivities over the JAK2 isoform by targeting several residues unique to JAK1, such as Arg-879 and Glu-966.
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
487.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK1 assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation at 10 uM pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
94.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK2 expressed in Sf21 cells assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation at 10 uM pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK3 assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation at 10 uM pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
85.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK1 assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK2 expressed in Sf21 cells assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Inhibition of human recombinant JAK3 assessed as reduction in Ulight-CAGAGAIETDKEYYTVKD phosphorylation pre-incubated before substrate addition and measured after 60 mins by LANCE detection method
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and preliminary biological evaluation of 4-aminopyrazole derivatives as novel and potent JAKs inhibitors.
Year : 2016
Volume : 24
Issue : 12
First Page : 2660
Last Page : 2672
Authors : Liang X, Huang Y, Zang J, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : JAKs inhibitors were widely applied in the treatment of immunodeficiency diseases, inflammation and cancers. We designed and synthesized a novel series of 4-aminopyrazole derivatives, which showed inhibitory potency against various JAKs. The in vitro protein kinase inhibition experiment indicated that compounds 17k, 17l, 17m and 17n could inhibit JAKs effectively. Among them, compound 17m possessed the highest protein kinase inhibitory rates (%) at 10μM, which were 97, 96 and 100 to JAK1, JAK2 and JAK3, respectively. Further evaluation revealed that the IC50 values of 17m against JAK1, JAK2 and JAK3 were 0.67μM, 0.098μM and 0.039μM, respectively. Moreover, western blotting results showed compound 17m could inhibit the phosphorylation of JAK2 in Hela cells effectively. The data supports the further investigation of these compounds as novel JAKs inhibitors.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
310.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
259.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
196.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
375.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
851.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
5.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
196.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
819.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Binding affinity to recombinant human CLK2 (D144 to R498 residues) expressed in bacterial expression system by KinomeScan assay
|
Homo sapiens
|
460.0
nM
|
|
Journal : Eur J Med Chem
Title : Novel CLK1 inhibitors based on N-aryloxazol-2-amine skeleton - A possible way to dual VEGFR2 TK/CLK ligands.
Year : 2017
Volume : 126
First Page : 754
Last Page : 761
Authors : Murár M, Dobiaš J, Šramel P, Addová G, Hanquet G, Boháč A.
Abstract : Inhibitors of CLK protein kinases suppress cell growth and induce apoptosis by modulating pre-mRNA splicing in cancer. CLK family kinases are also involved in alternative splicing and RNA processing in Duchenne muscular dystrophy, Alzheimer's disease, HIV-1, and influenza virus. Small inhibitors are valuable tools for better understanding the molecular mechanisms of splicing and may serve as seeds for a novel class of therapeutics.Here we describe a discovery of four novel CLK1 inhibitors possessing N-aryloxazol-2-amine skeleton. Their activity against CLK1 (IC50: 20, 30, 40 and 80 nM) and some other CMGC kinases, predicted CLK binding poses, synthesis and physico-chemical characteristics are also stated. Additionally analysis of all PDB available CLK structures and interactions of their ligands was performed. There are only few powerful dual CLK/VEGFR inhibitors known in the literature. We proposed that our inhibitors have similar binding places and interactions in CLK1, 3 and VEGFR2 TK mostly due to the joint N-aryloxazol-2-amine pharmacophoric fragment. One of our N-aryloxazol-2-amines already proved a good activity against both VEGFR2 and CLK1 enzymes (23/80 nM, resp). We proposed that the presented class of compounds has a potential to be developed in dual VEGFR2/CLK clinical compounds with prospective synergy to treat cancer.
|
Inhibition of recombinant human JAK1 using 5'FAM-KKSRGDYMTMQID as substrate in presence of 1 mM ATP by mobility shift assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Year : 2018
Volume : 61
Issue : 3
First Page : 1130
Last Page : 1152
Authors : Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, Mitton-Fry MJ, Johnson TA, TenBrink RE, Arnold EP, Basak A, Heasley SE, Kwon S, Langille J, Parikh MD, Griffin SH, Casavant JM, Duclos BA, Fenwick AE, Harris TM, Han S, Caspers N, Dowty ME, Yang X, Banker ME, Hegen M, Symanowicz PT, Li L, Wang L, Lin TH, Jussif J, Clark JD, Telliez JB, Robinson RP, Unwalla R.
Abstract : Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
|
Inhibition of recombinant human JAK2 using FITC-KGGEEEEYFELVKK as substrate in presence of 1 mM ATP by mobility shift assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Year : 2018
Volume : 61
Issue : 3
First Page : 1130
Last Page : 1152
Authors : Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, Mitton-Fry MJ, Johnson TA, TenBrink RE, Arnold EP, Basak A, Heasley SE, Kwon S, Langille J, Parikh MD, Griffin SH, Casavant JM, Duclos BA, Fenwick AE, Harris TM, Han S, Caspers N, Dowty ME, Yang X, Banker ME, Hegen M, Symanowicz PT, Li L, Wang L, Lin TH, Jussif J, Clark JD, Telliez JB, Robinson RP, Unwalla R.
Abstract : Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
|
Inhibition of JAK1/TYK2 in human whole blood assessed as reduction in IFNalpha induced STAT3 phosphorylation preincubated for 45 mins followed by IFNalpha addition measured after 15 mins by flow cytometric analysis
|
Homo sapiens
|
194.0
nM
|
|
Journal : J Med Chem
Title : Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Year : 2018
Volume : 61
Issue : 3
First Page : 1130
Last Page : 1152
Authors : Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, Mitton-Fry MJ, Johnson TA, TenBrink RE, Arnold EP, Basak A, Heasley SE, Kwon S, Langille J, Parikh MD, Griffin SH, Casavant JM, Duclos BA, Fenwick AE, Harris TM, Han S, Caspers N, Dowty ME, Yang X, Banker ME, Hegen M, Symanowicz PT, Li L, Wang L, Lin TH, Jussif J, Clark JD, Telliez JB, Robinson RP, Unwalla R.
Abstract : Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
|
Inhibition of JAK2 in CD34+ human whole blood assessed as reduction in EOP induced STAT5 phosphorylation preincubated for 45 mins followed by EOP addition measured after 15 mins by flow cytometric analysis
|
Homo sapiens
|
677.0
nM
|
|
Journal : J Med Chem
Title : Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Year : 2018
Volume : 61
Issue : 3
First Page : 1130
Last Page : 1152
Authors : Vazquez ML, Kaila N, Strohbach JW, Trzupek JD, Brown MF, Flanagan ME, Mitton-Fry MJ, Johnson TA, TenBrink RE, Arnold EP, Basak A, Heasley SE, Kwon S, Langille J, Parikh MD, Griffin SH, Casavant JM, Duclos BA, Fenwick AE, Harris TM, Han S, Caspers N, Dowty ME, Yang X, Banker ME, Hegen M, Symanowicz PT, Li L, Wang L, Lin TH, Jussif J, Clark JD, Telliez JB, Robinson RP, Unwalla R.
Abstract : Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
|
Inhibition of human JAK2 using poly[Glu:Tyr] as substrate in presence of [gamma-33P]-ATP
|
Homo sapiens
|
0.056
nM
|
|
Journal : J Med Chem
Title : Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat.
Year : 2017
Volume : 60
Issue : 20
First Page : 8336
Last Page : 8357
Authors : Yao L, Mustafa N, Tan EC, Poulsen A, Singh P, Duong-Thi MD, Lee JXT, Ramanujulu PM, Chng WJ, Yen JJY, Ohlson S, Dymock BW.
Abstract : Concomitant inhibition of multiple oncogenic pathways is a desirable goal in cancer therapy. To achieve such an outcome with a single molecule would simplify treatment regimes. Herein the core features of ruxolitinib (1), a marketed JAK1/2 inhibitor, have been merged with the HDAC inhibitor vorinostat (2), leading to new molecules that are bispecific targeted JAK/HDAC inhibitors. A preferred pyrazole substituted pyrrolopyrimidine, 24, inhibits JAK1 and HDACs 1, 2, 3, 6, and 10 with IC50 values of less than 20 nM, is <100 nM potent against JAK2 and HDAC11, and is selective for the JAK family against a panel of 97 kinases. Broad cellular antiproliferative potency of 24 is supported by demonstration of JAK-STAT and HDAC pathway blockade in hematological cell lines. Methyl analogue 45 has an even more selective profile. This study provides new leads for assessment of JAK and HDAC pathway dual inhibiton achieved with a single molecule.
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
38.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.
Year : 2018
Volume : 61
Issue : 12
First Page : 5235
Last Page : 5244
Authors : Grimster NP, Anderson E, Alimzhanov M, Bebernitz G, Bell K, Chuaqui C, Deegan T, Ferguson AD, Gero T, Harsch A, Huszar D, Kawatkar A, Kettle JG, Lyne P, Read JA, Rivard Costa C, Ruston L, Schroeder P, Shi J, Su Q, Throner S, Toader D, Vasbinder M, Woessner R, Wang H, Wu A, Ye M, Zheng W, Zinda M.
Abstract : Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
60.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors.
Year : 2018
Volume : 61
Issue : 12
First Page : 5235
Last Page : 5244
Authors : Grimster NP, Anderson E, Alimzhanov M, Bebernitz G, Bell K, Chuaqui C, Deegan T, Ferguson AD, Gero T, Harsch A, Huszar D, Kawatkar A, Kettle JG, Lyne P, Read JA, Rivard Costa C, Ruston L, Schroeder P, Shi J, Su Q, Throner S, Toader D, Vasbinder M, Woessner R, Wang H, Wu A, Ye M, Zheng W, Zinda M.
Abstract : Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).
|
Inhibition of human JAK2 using poly[Glu:Tyr] (4:1) as substrate in presence of [gamma33P]-ATP
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design and synthesis of triple inhibitors of janus kinase (JAK), histone deacetylase (HDAC) and Heat Shock Protein 90 (HSP90).
Year : 2018
Volume : 28
Issue : 8
First Page : 1357
Last Page : 1362
Authors : Yao L, Ohlson S, Dymock BW.
Abstract : Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90). Although these enzymes have totally different functions they are related through inter-dependent pathways in the developing cancer cell. Synthesis of several complex multi-inhibiting ligands are presented along with initial enzyme inhibition data against 3 biological target classes of interest. A lead compound, 47, was discovered which had low micromolar activity for all 3 targets. Further development of these complex trispecific designed multiple ligands could result in a 'transient drug', an alternative combination therapy for treating cancer mediated via a single molecule.
|
Inhibition of human JAK2 using poly[Glu:Tyr] (4:1) as substrate in presence of [gamma-33P]ATP
|
Homo sapiens
|
0.056
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6).
Year : 2018
Volume : 28
Issue : 15
First Page : 2636
Last Page : 2640
Authors : Yao L, Ramanujulu PM, Poulsen A, Ohlson S, Dymock BW.
Abstract : Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41 pM and a sub-nanomolar IC50 against HDAC6 of 200 pM. Binding models show a good fit into both JAK2 and HDAC6.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
3.72
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of recombinant human N-terminal epitope-tagged JAK2 (828 to 1132 residues) expressed in baculovirus infected Sf21 insect cells using EQEDEPEGDYFEWLE as substrate after 1 hr by homogeneous time-resolved fluorescence assay
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Binding affinity to human recombinant N-terminal hexahistidine tagged JAK2 JH1 catalytic domain (835 to 1132 residues) expressed in baculovirus infected Sf9 cells assessed as dissociation constant by surface plasmon resonance assay
|
Homo sapiens
|
28.2
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Inhibition of human recombinant N-terminal hexahistidine tagged JAK1 JH1 catalytic domain (854 to 1154 residues) expressed in baculovirus infected Sf9 cells using Tyr6 peptide as substrate incubated for 30 secs under shaking condition measured after 1 hr by Z'-LYTE assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Inhibition of human recombinant N-terminal hexahistidine tagged JAK2 JH1 catalytic domain (835 to 1132 residues) expressed in baculovirus infected Sf9 cells using Tyr6 peptide as substrate incubated for 30 secs under shaking condition measured after 1 hr by Z'-LYTE assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Inhibition of human recombinant C-terminal hexahistidine tagged JAK3 JH1 catalytic domain (811 to 1124 residues) expressed in baculovirus infected Sf9 cells using Tyr6 peptide as substrate incubated for 30 secs under shaking condition measured after 1 hr by Z'-LYTE assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Inhibition of TYK2 (unknown origin) using peptide as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.
Year : 2019
Volume : 29
Issue : 12
First Page : 1507
Last Page : 1513
Authors : Wang W, Diao Y, Li W, Luo Y, Yang T, Zhao Y, Qi T, Xu F, Ma X, Ge H, Liang Y, Zhao Z, Liang X, Wang R, Zhu L, Li H, Xu Y.
Abstract : Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC<sub>50</sub> = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC<sub>50</sub> = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
|
Inhibition of recombinant human HDAC6 using p53 (379 to 382 residues) derived fluorogenic peptide RHKKAc as substrate
|
Homo sapiens
|
15.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies.
Year : 2019
Volume : 62
Issue : 8
First Page : 3898
Last Page : 3923
Authors : Liang X, Zang J, Li X, Tang S, Huang M, Geng M, Chou CJ, Li C, Cao Y, Xu W, Liu H, Zhang Y.
Abstract : Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2<sup>V617F</sup> mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.
|
Synergistic antiproliferative activity against HEL cells harboring JAK2 V617F mutant assessed as reduction in cell viability after 48 hrs in presence of SAHA by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies.
Year : 2019
Volume : 62
Issue : 8
First Page : 3898
Last Page : 3923
Authors : Liang X, Zang J, Li X, Tang S, Huang M, Geng M, Chou CJ, Li C, Cao Y, Xu W, Liu H, Zhang Y.
Abstract : Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2<sup>V617F</sup> mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.
Year : 2019
Volume : 62
Issue : 12
First Page : 5673
Last Page : 5724
Authors : Gehringer M, Laufer SA.
Abstract : Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
9.0
nM
|
|
Journal : J Med Chem
Title : Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.
Year : 2019
Volume : 62
Issue : 12
First Page : 5673
Last Page : 5724
Authors : Gehringer M, Laufer SA.
Abstract : Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
487.0
nM
|
|
Journal : J Med Chem
Title : Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.
Year : 2019
Volume : 62
Issue : 12
First Page : 5673
Last Page : 5724
Authors : Gehringer M, Laufer SA.
Abstract : Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
|
Inhibition of TYK2 (unknown origin)
|
Homo sapiens
|
30.0
nM
|
|
Journal : J Med Chem
Title : Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.
Year : 2019
Volume : 62
Issue : 12
First Page : 5673
Last Page : 5724
Authors : Gehringer M, Laufer SA.
Abstract : Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting noncatalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of noncatalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads-beyond α,β-unsaturated amides-recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and of case studies illustrating applications in medicinal chemistry and chemical biology.
|
Inhibition of JAK1 (unknown origin)
|
Homo sapiens
|
3.3
nM
|
|
Journal : J Med Chem
Title : The Exploration of Chirality for Improved Druggability within the Human Kinome.
Year : 2020
Volume : 63
Issue : 2
First Page : 441
Last Page : 469
Authors : Saha D, Kharbanda A, Yan W, Lakkaniga NR, Frett B, Li HY.
Abstract : Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
|
Inhibition of JAK2 (unknown origin)
|
Homo sapiens
|
2.8
nM
|
|
Journal : J Med Chem
Title : The Exploration of Chirality for Improved Druggability within the Human Kinome.
Year : 2020
Volume : 63
Issue : 2
First Page : 441
Last Page : 469
Authors : Saha D, Kharbanda A, Yan W, Lakkaniga NR, Frett B, Li HY.
Abstract : Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
428.0
nM
|
|
Journal : J Med Chem
Title : The Exploration of Chirality for Improved Druggability within the Human Kinome.
Year : 2020
Volume : 63
Issue : 2
First Page : 441
Last Page : 469
Authors : Saha D, Kharbanda A, Yan W, Lakkaniga NR, Frett B, Li HY.
Abstract : Chirality is important in drug discovery because stereoselective drugs can ameliorate therapeutic difficulties including adverse toxicity and poor pharmacokinetic profiles. The human kinome, a major druggable enzyme class has been exploited to treat a wide range of diseases. However, many kinase inhibitors are planar and overlap in chemical space, which leads to selectivity and toxicity issues. By exploring chirality within the kinome, a new iteration of kinase inhibitors is being developed to better utilize the three-dimensional nature of the kinase active site. Exploration into novel chemical space, in turn, will also improve drug solubility and pharmacokinetic profiles. This perspective explores the role of chirality to improve kinome druggability and will serve as a resource for pioneering kinase inhibitor development to address current therapeutic needs.
|
Inhibition of recombinant human N-terminal GST-tagged JAK1 (866 to 1154 residues) expressed in insect cells using FITC-labeled C6-KKHTDDGYMPMSPGVA-NH peptide as substrate after 10 mins in presence of 5 mM ATP by caliper mobility shift assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.
Year : 2020
Volume : 63
Issue : 9
First Page : 4517
Last Page : 4527
Authors : Su Q, Banks E, Bebernitz G, Bell K, Borenstein CF, Chen H, Chuaqui CE, Deng N, Ferguson AD, Kawatkar S, Grimster NP, Ruston L, Lyne PD, Read JA, Peng X, Pei X, Fawell S, Tang Z, Throner S, Vasbinder MM, Wang H, Winter-Holt J, Woessner R, Wu A, Yang W, Zinda M, Kettle JG.
Abstract : JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.
|
Inhibition of recombinant human N-terminal GST-tagged JAK2 (831 to 1132 residues) expressed in insect cells using 5FAM-labeled GEEPLYWSFPAKKK-NH2 peptide as substrate after 10 mins in presence of 5 mM ATP by caliper mobility shift assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.
Year : 2020
Volume : 63
Issue : 9
First Page : 4517
Last Page : 4527
Authors : Su Q, Banks E, Bebernitz G, Bell K, Borenstein CF, Chen H, Chuaqui CE, Deng N, Ferguson AD, Kawatkar S, Grimster NP, Ruston L, Lyne PD, Read JA, Peng X, Pei X, Fawell S, Tang Z, Throner S, Vasbinder MM, Wang H, Winter-Holt J, Woessner R, Wu A, Yang W, Zinda M, Kettle JG.
Abstract : JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.
|
Inhibition of human JAK1 using GEEPLYWSFPAKKK as substrate measured after 40 mins in presence of ATP by scintillation counting method
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Inhibition of recombinant human C-terminal 6His-tagged JAK2 (808 to end amino acids) expressed in Sf21 cells measured after 1 hr in presence of ATP by TR-FRET assay
|
Homo sapiens
|
4.1
nM
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Inhibition of JAK3 (unknown origin) measured after 1 hr in presence of ATP by TR-FRET assay
|
Homo sapiens
|
428.0
nM
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Inhibition of JAK2 V617F mutant expressed in mouse BaF3 cells cells assessed as reduction in cell viability
|
Mus musculus
|
186.0
nM
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Cytotoxicity against wild-type human HCC827 cells at 30 uM measured after 72 hrs by MTT assay
|
Homo sapiens
|
16.6
%
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Cytotoxicity against human gefitinib-resistant HCC827 cells at 30 uM measured after 72 hrs by MTT assay
|
Homo sapiens
|
57.1
%
|
|
Journal : Bioorg Med Chem
Title : The discovery of 2,5-isomers of triazole-pyrrolopyrimidine as selective Janus kinase 2 (JAK2) inhibitors versus JAK1 and JAK3.
Year : 2016
Volume : 24
Issue : 21
First Page : 5036
Last Page : 5046
Authors : Lee SM, Yoon KB, Lee HJ, Kim J, Chung YK, Cho WJ, Mukai C, Choi S, Kang KW, Han SY, Ko H, Kim YC.
Abstract : Members of the Janus kinase (JAK) family are potential therapeutic targets. Abnormal signaling by mutant JAK2 is related to hematological malignancy, such as myeloproliferative neoplasms (MPNs), and tyrosine kinase inhibitor (TKI)-resistance in non-small cell lung cancer (NSCLC). We discovered a potent and highly selective inhibitor of JAK2 over JAK1 and -3 based on the structure of 4-(2,5-triazole)-pyrrolopyrimidine. Among all triazole compounds tested, 2,5-triazole regioisomers more effectively inhibited JAK2 kinase activity than isomers with substitutions of various alkyl groups at the R<sub>2</sub> position, except for methyl-substituted 1,5-triazole, which was more potent than the corresponding 1,4- and 2,5-triazoles. None of the synthesized 1,4-isomers inhibited all three JAK family members. Compounds with phenyl or tolyl group substituents at the R<sub>1</sub> position were completely inactive compared with the corresponding analogues with a methyl substituted at the R<sub>1</sub> position. As a result of this structure-activity relationship, 54, which is substituted with a cyclopropylmethyl moiety, exhibited significant inhibitory activity and selectivity (IC<sub>50</sub>=41.9nM, fold selectivity JAK1/2 10.6 and JAK3/2 58.1). Compound 54 also exhibited an equivalent inhibition of wild type JAK2 and the V617F mutant. Moreover, 54 inhibited the proliferation of HEL 92.1.7 cells, which carry JAK2 V617F, and gefitinib-resistant HCC827 cells. Compound 54 also suppressed STAT3 phosphorylation at Y705.
|
Inhibition of human recombinant JAK1 using Ulight-CAGAGAIETDKEYYTVKD as substrate at 20 nM by LANCE assay relative to control
|
Homo sapiens
|
97.0
%
|
|
Journal : ACS Med Chem Lett
Title : Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1<i>H</i>)-pyrazole Derivatives as JAKs Inhibitors.
Year : 2016
Volume : 7
Issue : 10
First Page : 950
Last Page : 955
Authors : Liang X, Zang J, Zhu M, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>-<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC<sub>50</sub> values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC<sub>50</sub>: 0.35 μM) and K562 (IC<sub>50</sub>: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.
|
Inhibition of human recombinant JAK2 using Ulight-CAGAGAIETDKEYYTVKD as substrate at 20 nM by LANCE assay relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : ACS Med Chem Lett
Title : Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1<i>H</i>)-pyrazole Derivatives as JAKs Inhibitors.
Year : 2016
Volume : 7
Issue : 10
First Page : 950
Last Page : 955
Authors : Liang X, Zang J, Zhu M, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>-<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC<sub>50</sub> values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC<sub>50</sub>: 0.35 μM) and K562 (IC<sub>50</sub>: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.
|
Inhibition of human recombinant JAK3 using Ulight-CAGAGAIETDKEYYTVKD as substrate at 20 nM by LANCE assay relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : ACS Med Chem Lett
Title : Design, Synthesis, and Antitumor Evaluation of 4-Amino-(1<i>H</i>)-pyrazole Derivatives as JAKs Inhibitors.
Year : 2016
Volume : 7
Issue : 10
First Page : 950
Last Page : 955
Authors : Liang X, Zang J, Zhu M, Gao Q, Wang B, Xu W, Zhang Y.
Abstract : Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>-<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC<sub>50</sub> values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC<sub>50</sub>: 0.35 μM) and K562 (IC<sub>50</sub>: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib.
|
Inhibition of human JAK1 (837 to 1142 residues) expressed in baculovirus infected Sf9 insect cells using EQEDEPEGDYFEWLE as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
3.3
nM
|
|
Journal : Bioorg Med Chem
Title : The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1497
Last Page : 1508
Authors : Egyed A, Bajusz D, Keserű GM.
Abstract : Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by water molecules available in the binding site. Simulation of water networks in combination with docking enabled us to identify the key waters and to optimize our primary hit into a low nanomolar JAK2 lead with promising selectivity over JAK1.
|
Inhibition of human JAK2 (828 to 1132 residues) expressed in baculovirus infected Sf9 insect cells using EQEDEPEGDYFEWLE as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
2.8
nM
|
|
Journal : Bioorg Med Chem
Title : The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors.
Year : 2019
Volume : 27
Issue : 8
First Page : 1497
Last Page : 1508
Authors : Egyed A, Bajusz D, Keserű GM.
Abstract : Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by water molecules available in the binding site. Simulation of water networks in combination with docking enabled us to identify the key waters and to optimize our primary hit into a low nanomolar JAK2 lead with promising selectivity over JAK1.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
78.76
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.28
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.66
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.16
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.16
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Inhibition of recombinant epitope tagged JAK3 (718 to 1124 residues) (unknown origin) using Chk2 as substrate by HTRF assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and pharmacological evaluation of 4- or 6-phenyl-pyrimidine derivatives as novel and selective Janus kinase 3 inhibitors.
Year : 2020
Volume : 191
First Page : 112148
Last Page : 112148
Authors : Shu L,Chen C,Huan X,Huang H,Wang M,Zhang J,Yan Y,Liu J,Zhang T,Zhang D
Abstract : As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases.
|
Inhibition of recombinant epitope tagged JAK2 (828 to 1132 residues) (unknown origin) using Chk2 as substrate by HTRF assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and pharmacological evaluation of 4- or 6-phenyl-pyrimidine derivatives as novel and selective Janus kinase 3 inhibitors.
Year : 2020
Volume : 191
First Page : 112148
Last Page : 112148
Authors : Shu L,Chen C,Huan X,Huang H,Wang M,Zhang J,Yan Y,Liu J,Zhang T,Zhang D
Abstract : As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases.
|
Inhibition of recombinant epitope tagged JAK1 (837 to 1142 residues) (unknown origin) using Chk2 as substrate by HTRF assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and pharmacological evaluation of 4- or 6-phenyl-pyrimidine derivatives as novel and selective Janus kinase 3 inhibitors.
Year : 2020
Volume : 191
First Page : 112148
Last Page : 112148
Authors : Shu L,Chen C,Huan X,Huang H,Wang M,Zhang J,Yan Y,Liu J,Zhang T,Zhang D
Abstract : As non-receptor tyrosine kinases, Janus kinases (JAKs) have become an attractive target for the treatment of autoimmune diseases and cancers. JAKs play a pivotal role in innate immunity, inflammation, and hematopoiesis by mediating the signaling of numerous cytokines, growth factors, and interferons (IFNs). Selective inhibitors of a variety of JAK members are expected to inhibit pro-inflammatory cytokine-mediated inflammation and immune responses, while preventing targeting other subtypes of JAKs. In this work, poorly selective compounds based on 4- or 6-phenyl-pyrimidine derivatives have been improved to highly potent and selective compounds by designing a covalent binding tether, which attaches to the unique cysteine (Cys909) residue in JAK3. Compound 12 exhibited potent JAK3 inhibitory activity (IC = 1.7 nM) with an excellent selectivity profile when compared to the other JAK isoforms (>588-fold). In a cellular assay, compound 12 strongly inhibited JAK3-dependent signaling and T cell proliferation. Moreover, in vivo data revealed that compound 12 significantly suppressed oxazolone (OXZ)-induced delayed hypersensitivity responses in Balb/c mice. Compound 12 also displayed decent pharmacokinetic properties and was suitable for in vivo use. Taken together, these results indicated that compound 12 may be a promising tool compound as a selective JAK3 inhibitor for treating autoimmune diseases.
|
Inhibition of human JAK2 by radiometric assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : J Med Chem
Title : Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.
Year : 2021
Volume : 64
Issue : 4.0
First Page : 2228
Last Page : 2241
Authors : Davis RR,Li B,Yun SY,Chan A,Nareddy P,Gunawan S,Ayaz M,Lawrence HR,Reuther GW,Lawrence NJ,Schönbrunn E
Abstract : The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.
|
Growth inhibition of human UKE-1 cells incubated for 72 hrs by Cell-titer blue assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.
Year : 2021
Volume : 64
Issue : 4.0
First Page : 2228
Last Page : 2241
Authors : Davis RR,Li B,Yun SY,Chan A,Nareddy P,Gunawan S,Ayaz M,Lawrence HR,Reuther GW,Lawrence NJ,Schönbrunn E
Abstract : The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.
|
Inhibition of recombinant human JAK2 JH1 domain expressed in baculovirus infected insect cells using poly-Glu-Tyr (51 to 68 residues) as substrate incubated for 1 hr in presence of ATP by ADP-Glo assay
|
Homo sapiens
|
18.06
nM
|
|
Journal : RSC Med Chem
Title : Discovery of novel JAK2 and EGFR inhibitors from a series of thiazole-based chalcone derivatives
Year : 2021
Volume : 12
Issue : 3.0
First Page : 430
Last Page : 438
Authors : Sanachai, Kamonpan, Aiebchun, Thitinan, Mahalapbutr, Panupong, Seetaha, Supaphorn, Tabtimmai, Lueacha, Maitarad, Phornphimon, Xenikakis, Iakovos, Geronikaki, Athina, Choowongkomon, Kiattawee, Rungrotmongkol, Thanyada
Abstract : The Janus kinase (JAK) and epidermal growth factor receptor (EGFR) have been considered as potential targets for cancer therapy due to their role in regulating proliferation and survival of cancer cells. In the present study, the aromatic alkyl-amino analogs of thiazole-based chalcone were selected to experimentally and theoretically investigate their inhibitory activity against JAK2 and EGFR proteins as well as their anti-cancer effects on human cancer cell lines expressing JAK2 (TF1 and HEL) and EGFR (A549 and A431). In vitro cytotoxicity screening results demonstrated that the HEL erythroleukemia cell line was susceptible to compounds 11 and 12, whereas the A431 lung cancer cell line was vulnerable to compound 25. However, TF1 and A549 cells were not sensitive to our thiazole derivatives. From kinase inhibition assay results, compound 25 was found to be a dual inhibitor against JAK2 and EGFR, whereas compounds 11 and 12 selectively inhibited the JAK2 protein. According to the molecular docking analysis, compounds 11, 12 and 25 formed hydrogen bonds with the hinge region residues Lys857, Leu932 and Glu930 and hydrophobically came into contact with Leu983 at the catalytic site of JAK2, while compound 25 formed a hydrogen bond with Met769 at the hinge region, Lys721 near a glycine loop, and Asp831 at the activation loop of EGFR. Altogether, these potent thiazole derivatives, following Lipinski's rule of five, could likely be developed as a promising JAK2/EGFR targeted drug(s) for cancer therapy.
|
Inhibition of JAK1 (unknown origin) at 1 uM by ELISA
|
Homo sapiens
|
80.4
%
|
|
|
Inhibition of JAK2 (unknown origin) at 1 uM by ELISA
|
Homo sapiens
|
91.7
%
|
|
|
Inhibition of JAK3 (unknown origin) at 1 uM by ELISA
|
Homo sapiens
|
78.5
%
|
|
|
Inhibition of JAK2 (unknown origin) preincubated for 60 mins followed by reagent A addition and measured after 60 mins in presence of ATP by using microplate reader method
|
Homo sapiens
|
2.9
nM
|
|
|
Inhibition of JAK1 (unknown origin) preincubated for 60 mins followed by reagent A addition and measured after 60 mins in presence of ATP by using microplate reader method
|
Homo sapiens
|
1.1
nM
|
|
|
Inhibition of JAK3 (unknown origin) preincubated for 60 mins followed by reagent A addition and measured after 60 mins in presence of ATP by using microplate reader method
|
Homo sapiens
|
20.7
nM
|
|
|
Inhibition of TYK2 (unknown origin) incubated for 40 min in presence of ATP by microplate reader analysis
|
Homo sapiens
|
10.3
nM
|
|
