|
Inhibition of CDK2/Cyclin A by radiometric assay
|
None
|
47.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Inhibition of CDK1/Cyclin B by radiometric assay
|
None
|
190.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Inhibition of CDK4/Cyclin D1
|
None
|
67.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Antiproliferative activity against human HCT116 cells assessed as cell viability after 72 hrs by alamar blue assay
|
Homo sapiens
|
82.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Antiproliferative activity against human A2780 cells assessed as cell viability after 72 hrs by alamar blue assay
|
Homo sapiens
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Antiproliferative activity against human MRC5 cells assessed as cell viability after 72 hrs by alamar blue assay
|
Homo sapiens
|
980.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
Year : 2008
Volume : 51
Issue : 16
First Page : 4986
Last Page : 4999
Authors : Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ.
Abstract : The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.
|
Binding constant for CDC2L1 kinase domain
|
None
|
8.4
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 DYRK1A 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 ERK8 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 PFTAIRE2 kinase domain
|
None
|
62.0
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 CASK kinase domain
|
None
|
24.0
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 CDC2L5 kinase domain
|
None
|
3.2
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 CLK1 kinase domain
|
None
|
990.0
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 PCTK2 kinase domain
|
None
|
0.95
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 CDK4-cyclinD1 kinase domain
|
None
|
20.0
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 CDK4-cyclinD3 kinase domain
|
None
|
12.0
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 CDK3 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 CDK9 kinase domain
|
None
|
5.8
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 CDK2 kinase domain
|
None
|
30.0
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 CDK7 kinase domain
|
None
|
2.8
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 GSK3B kinase domain
|
None
|
11.0
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 PCTK3 kinase domain
|
None
|
14.0
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 ERK5 kinase domain
|
None
|
42.0
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 CDKL5 kinase domain
|
None
|
2.6
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 CLK3 kinase domain
|
None
|
370.0
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 DYRK1B 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 CDK5 kinase domain
|
None
|
700.0
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 MAK 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 PCTK1 kinase domain
|
None
|
1.1
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 PFTK1 kinase domain
|
None
|
16.0
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 ICK kinase domain
|
None
|
8.3
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
|
50.0
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
|
57.0
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 GSK3A kinase domain
|
None
|
23.0
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 TAOK1 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 CDC2L2 kinase domain
|
None
|
5.2
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 CDK2/cyclin A (unknown origin) by radiometric filter binding assay
|
Homo sapiens
|
47.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK1/cyclin B (unknown origin) by radiometric filter binding assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK5/p35 (unknown origin) by DELFIA assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK9/cyclin T (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by Alamar blue assay
|
Homo sapiens
|
80.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK4/cyclin D1 (unknown origin) by ELISA
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK6/cyclin D3 (unknown origin) by ELISA
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of GSK3beta (unknown origin) by radiometric filter binding assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cyclin dependent kinase (CDK) inhibitors as anticancer drugs.
Year : 2015
Volume : 25
Issue : 17
First Page : 3420
Last Page : 3435
Authors : Sánchez-Martínez C, Gelbert LM, Lallena MJ, de Dios A.
Abstract : Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described.
|
Inhibition of CDK9/cyclin T (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of human full length C-terminal His6-tagged CDK1/N-terminal GST-tagged cyclin B expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
190.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of human full length C-terminal His6-tagged CDK2/N-terminal GST-tagged cyclin A expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
44.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human full length C-terminal His6-tagged CDK2/N-terminal GST-tagged cyclin E expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
510.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human full length N-terminal His6-tagged CDK5/N-terminal GST-tagged p25 expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
18.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human full length C-terminal His6-tagged CDK9/cyclin T1 expressed in baculovirus infected Sf21 insect cells using PDKtide as substrate
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of recombinant human N-terminal GST-tagged CDK4/cyclin D1 expressed in baculovirus infected sf cells
|
Homo sapiens
|
67.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
Inhibition of CDK6/cyclin D (unknown origin)
|
Homo sapiens
|
660.0
nM
|
|
Journal : J Med Chem
Title : Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.
Year : 2016
Volume : 59
Issue : 19
First Page : 8667
Last Page : 8684
Authors : Sonawane YA, Taylor MA, Napoleon JV, Rana S, Contreras JI, Natarajan A.
Abstract : Cyclin dependent kinase (CDK) inhibitors have been the topic of intense research for nearly 2 decades due to their widely varied and critical functions within the cell. Recently CDK9 has emerged as a druggable target for the development of cancer therapeutics. CDK9 plays a crucial role in transcription regulation; specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Focused chemical libraries based on a plethora of scaffolds have resulted in mixed success with regard to the development of selective CDK9 inhibitors. Here we review the regulation of CDK9, its cellular functions, and common core structures used to target CDK9, along with their selectivity profile and efficacy in vitro and in vivo.
|
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
|
250.0
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
|
203.0
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
|
8.0
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
|
7.0
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
|
169.0
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
|
131.0
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
|
7.0
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
|
12.0
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
|
33.0
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
|
58.0
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
|
253.0
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
|
933.0
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
|
737.0
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.
|
Protection against cisplatin-induced cell death in neonatal mouse HEI-OC1 cells assessed as reduction in caspase-3/7 activity
|
Mus musculus
|
380.0
nM
|
|
Journal : J Med Chem
Title : Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.
Year : 2018
Volume : 61
Issue : 17
First Page : 7700
Last Page : 7709
Authors : Hazlitt RA, Teitz T, Bonga JD, Fang J, Diao S, Iconaru L, Yang L, Goktug AN, Currier DG, Chen T, Rankovic Z, Min J, Zuo J.
Abstract : There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogues of AT7519 and identified analogue 7, which exhibited an improved therapeutic index. When delivered locally, analogue 7 and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two additional compounds that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
|
Protection against cisplatin-induced toxicity in P3 mouse cochlear explants assessed as increase in outer hair cell count incubated for 24 hrs by phalloidin staining based confocal microscopy
|
Mus musculus
|
25.0
nM
|
|
Journal : J Med Chem
Title : Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.
Year : 2018
Volume : 61
Issue : 17
First Page : 7700
Last Page : 7709
Authors : Hazlitt RA, Teitz T, Bonga JD, Fang J, Diao S, Iconaru L, Yang L, Goktug AN, Currier DG, Chen T, Rankovic Z, Min J, Zuo J.
Abstract : There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogues of AT7519 and identified analogue 7, which exhibited an improved therapeutic index. When delivered locally, analogue 7 and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two additional compounds that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
|
Inhibition of C-terminal His6-tagged human full length CDK2/N-terminal GST-tagged human full length Cyclin A using histone H1 and [gamma-32P]-ATP incubated for 30 mins by phosphorimage based assay
|
Homo sapiens
|
47.0
nM
|
|
Journal : J Med Chem
Title : Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.
Year : 2018
Volume : 61
Issue : 17
First Page : 7700
Last Page : 7709
Authors : Hazlitt RA, Teitz T, Bonga JD, Fang J, Diao S, Iconaru L, Yang L, Goktug AN, Currier DG, Chen T, Rankovic Z, Min J, Zuo J.
Abstract : There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin. Moreover, we screened 36 analogues of AT7519 and identified analogue 7, which exhibited an improved therapeutic index. When delivered locally, analogue 7 and AZD5438 both provided significant protection against cisplatin-induced ototoxicity in mice. Thus, we have identified two additional compounds that prevent cisplatin-induced ototoxicity in vivo and provided further evidence that CDK2 is a druggable target for treating cisplatin-induced ototoxicity.
|
Inhibition of CDK2 (unknown origin)
|
Homo sapiens
|
47.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors.
Year : 2017
Volume : 142
First Page : 424
Last Page : 458
Authors : Kalra S, Joshi G, Munshi A, Kumar R.
Abstract : There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs. Computer-aided drug design (CADD) tools added a benefit to the design and development of new CDK inhibitors by studying the binding pattern of the inhibitors to the ATP binding domain of CDKs. Herein, we have attempted a comparative analysis of structural differences between several CDKs ATP binding sites and their inhibitor specificity by depicting the important ligand-receptor interactions for a particular CDK to be targeted. This perspective provides futuristic implications in the design of inhibitors considering the spatial features and structural insights of the specific CDK.
|
Inhibition of CDK9 (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors.
Year : 2017
Volume : 142
First Page : 424
Last Page : 458
Authors : Kalra S, Joshi G, Munshi A, Kumar R.
Abstract : There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs. Computer-aided drug design (CADD) tools added a benefit to the design and development of new CDK inhibitors by studying the binding pattern of the inhibitors to the ATP binding domain of CDKs. Herein, we have attempted a comparative analysis of structural differences between several CDKs ATP binding sites and their inhibitor specificity by depicting the important ligand-receptor interactions for a particular CDK to be targeted. This perspective provides futuristic implications in the design of inhibitors considering the spatial features and structural insights of the specific CDK.
|
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
|
9.78
%
|
|
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.
|
Antiproliferative activity against human AsPC1 cells after 72 hrs by prestoblue assay
|
Homo sapiens
|
533.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3736
Last Page : 3740
Authors : Rana S, Sonawane YA, Taylor MA, Kizhake S, Zahid M, Natarajan A.
Abstract : We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.
|
Antiproliferative activity against human BxPC3 cells after 72 hrs by prestoblue assay
|
Homo sapiens
|
640.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3736
Last Page : 3740
Authors : Rana S, Sonawane YA, Taylor MA, Kizhake S, Zahid M, Natarajan A.
Abstract : We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.
|
Antiproliferative activity against human MIAPaCa2 cells after 72 hrs by prestoblue assay
|
Homo sapiens
|
411.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3736
Last Page : 3740
Authors : Rana S, Sonawane YA, Taylor MA, Kizhake S, Zahid M, Natarajan A.
Abstract : We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.
|
Antiproliferative activity against human SUIT2 cells after 72 hrs by prestoblue assay
|
Homo sapiens
|
557.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3736
Last Page : 3740
Authors : Rana S, Sonawane YA, Taylor MA, Kizhake S, Zahid M, Natarajan A.
Abstract : We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.
|
Inhibition of CDK4/Cyclin D1 (unknown origin) using GST-tagged pRb (769 to 921 residues) as substrate measured after 30 mins by ELISA
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of recombinant human full-length C-terminal His6-tagged CDK9/human full-length untagged cyclin T1 expressed in baculovirus infected Sf21 insect cells using PDKtide as substrate
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of recombinant human full-length C-terminal His6-tagged CDK3/full-length human N-terminal GST-tagged Cyclin E expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate
|
Homo sapiens
|
360.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of recombinant full-length human C-terminal His6-tagged CDK1/human full-length N-terminal GST-tagged Cyclin B expressed in baculovirus infected Sf21 insect cells using histone H1 as substrate measured after 2 hrs in presence of gamma[32P] ATP by topcount scintillation counting method
|
Homo sapiens
|
210.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of human recombinant full-length N-terminal His6-tagged CDK5/recombinant human full-length N-terminal GST-tagged p35 using biotinylated-histone H1 as substrate after 30 mins by DELFIA
|
Homo sapiens
|
513.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of CDK6/Cyclin D3 (unknown origin) using GST-tagged pRb (769 to 921 residues) as substrate measured after 30 mins by ELISA
|
Homo sapiens
|
170.0
nM
|
|
Journal : J Med Chem
Title : Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update.
Year : 2019
Volume : 62
Issue : 9
First Page : 4233
Last Page : 4251
Authors : Tadesse S, Caldon EC, Tilley W, Wang S.
Abstract : Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.
|
Inhibition of recombinant GST-tagged human full length CDK14/cyclin Y (2 to end residues) preincubated for 30 mins by Lantha screen eu binding assay
|
Homo sapiens
|
19.8
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14.
Year : 2019
Volume : 29
Issue : 15
First Page : 1985
Last Page : 1993
Authors : Ferguson FM, Doctor ZM, Ficarro SB, Marto JA, Kim ND, Sim T, Gray NS.
Abstract : The TAIRE family of kinases are an understudied branch of the CDK kinase family, that have been implicated in a number of cancers. This manuscript describes the design, synthesis and SAR of covalent CDK14 inhibitors, culminating in identification of FMF-04-159-2, a potent, covalent CDK14 inhibitor with a TAIRE kinase biased selectivity profile.
|
Antiproliferative activity against human HCT116 cells assessed as reduction in cell viability after 72 hrs by cell titer glo-based luminescence assay
|
Homo sapiens
|
132.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis and structure activity relationships of a series of 4-amino-1H-pyrazoles as covalent inhibitors of CDK14.
Year : 2019
Volume : 29
Issue : 15
First Page : 1985
Last Page : 1993
Authors : Ferguson FM, Doctor ZM, Ficarro SB, Marto JA, Kim ND, Sim T, Gray NS.
Abstract : The TAIRE family of kinases are an understudied branch of the CDK kinase family, that have been implicated in a number of cancers. This manuscript describes the design, synthesis and SAR of covalent CDK14 inhibitors, culminating in identification of FMF-04-159-2, a potent, covalent CDK14 inhibitor with a TAIRE kinase biased selectivity profile.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.26
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.32
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
3.89
%
|
|
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
|
9.19
%
|
|
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
|
4.42
%
|
|
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
|
3.03
%
|
|
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
|
9.19
%
|
|
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
|
4.42
%
|
|
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
|
3.03
%
|
|
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.
|
Antiproliferative activity against AR-negative human PC3 cells assessed as reduction in cell viability after 5 days by CCK8 assay
|
Homo sapiens
|
710.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of selective mono or dual PROTAC degrader probe of CDK isoforms.
Year : 2020
Volume : 187
First Page : 111952
Last Page : 111952
Authors : Zhou F, Chen L, Cao C, Yu J, Luo X, Zhou P, Zhao L, Du W, Cheng J, Xie Y, Chen Y.
Abstract : Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC<sub>50</sub>: 62 nM) and CDK9 (DC<sub>50</sub>: 33 nM). In human prostate cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.
|
Inhibition of CDK4 (unknown origin)
|
Homo sapiens
|
18.0
nM
|
|
Journal : RSC Med Chem
Title : Online informatics resources to facilitate cancer target and chemical probe discovery
Year : 2020
Volume : 11
Issue : 6
First Page : 611
Last Page : 624
Authors : Yang, Xuan, Fu, Haian, Ivanov, Andrey A.
Abstract : The advances in cancer genomics, chemical biology, high-throughput screening technologies, and synthetic medicinal chemistry have tremendously expanded the biological space of cancer targets and chemical space of bioactive small molecules to interrogate oncogenic signaling. To explore and leverage these exponentially growing cancer-associated data, a great number of computational tools, databases, and algorithms have been developed. This review summarizes recent cancer-related web resources that allow researchers working at the interface of chemical, biological, and cancer genomics fields to integrate clinical and genomics data for specific actionable targets and selective chemical compounds to facilitate cancer therapeutic discovery.
|
Inhibition of CDK1 (unknown origin)
|
Homo sapiens
|
210.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK2 (unknown origin)
|
Homo sapiens
|
47.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK4 (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK5 (unknown origin)
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK6 (unknown origin)
|
Homo sapiens
|
170.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK9 (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.
Year : 2020
Volume : 63
Issue : 22
First Page : 13228
Last Page : 13257
Authors : Wu T,Qin Z,Tian Y,Wang J,Xu C,Li Z,Bian J
Abstract : Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).
|
Inhibition of CDK1/cyclin B1 (unknown origin) using FAM-labeled peptide and ATP as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
89.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK2/cyclin A2 (unknown origin) using FAM-labeled peptide and ATP as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Antiproliferative activity against human A2058 cells assessed as reduction in cell viability measured after 96 hrs by Celltiter-Glo luminescent assay
|
Homo sapiens
|
166.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK4/cyclin D3 (unknown origin) using FAM-labeled peptide and ATP as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
72.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK9/cyclin T1 (unknown origin) using FAM-labeled peptide and ATP as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of C-terminal His6-tagged human full length CDK1/N-terminal GST-tagged human full length cyclin B expressed in baculovirus infected Sf21 cells using histone H1 as substrate measured after 2 hrs in presence of ATP by radiometric filter-binding assay
|
Homo sapiens
|
210.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK2/cyclin A (unknown origin) using histone H1 as substrate measured after 4 hrs in presence of ATP by radiometric filter-binding assay
|
Homo sapiens
|
47.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK6/cyclin D3 (unknown origin) incubated for 30 mins in presence of ATP by fluorescence based analysis
|
Homo sapiens
|
170.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK3/cyclin E1 (unknown origin)
|
Homo sapiens
|
360.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK9/cyclin T1 (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Antiproliferative activity against human MV4-11 cells assessed as reduction in cell viability measured after 96 hrs by Celltiter-Glo luminescent assay
|
Homo sapiens
|
391.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Cytotoxicity against human MRC5 cells assessed as reduction in cell viability measured after 96 hrs by Celltiter-Glo luminescent assay
|
Homo sapiens
|
425.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Cytotoxicity against human LX2 cells assessed as inhibition of cell growth at 100 uM measured after 96 hrs by Celltiter-Glo luminescent assay
|
Homo sapiens
|
39.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK1/cyclin B (unknown origin)
|
Homo sapiens
|
210.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK2/cyclin A (unknown origin)
|
Homo sapiens
|
47.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK3/cyclin E (unknown origin)
|
Homo sapiens
|
360.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
|
Inhibition of CDK9/cyclin T (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, and biological evaluation of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives as potent CDK2 inhibitors.
Year : 2021
Volume : 215
First Page : 113281
Last Page : 113281
Authors : Lin T,Li J,Liu L,Li Y,Jiang H,Chen K,Xu P,Luo C,Zhou B
Abstract : Cyclin-dependent kinases play significant roles in cell cycle progression and are promising targets for cancer therapy. However, most potent CDK inhibitors lack the balance between efficacy and safety because of poor selectivity. Given the roles of CDK2 in tumorigenesis, selective CDK2 inhibition may provide therapeutic benefits against certain cancer. In this study, a series of 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives were designed, synthesized, and evaluated. The most selective compound DC-K2in212 in this series exhibited high potency towards CDK2 and had effective anti-proliferative activity against A2058 melanoma cell line and MV4-11 leukemia cell line while exhibiting low toxic effect on human normal cell lines MRC5 and LX2. The molecular modeling illustrated that compound DC-K2in212 had the similar binding mode with CDK2 as C-73, the most selective CDK2 inhibitor reported so far, which might account for selectivity against CDK2 over CDK1. Further biological studies revealed that compound DC-K2in212 suppressed CDK2-associated downstream signaling pathway, blocked cell cycle progression, and induced cellular apoptosis. Therefore, compound DC-K2in212 could serve as a potential CDK2 inhibitor for further development.
