|
Inhibition of Cyclin-dependent kinase 4-cyclinD
|
None
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.
Year : 2005
Volume : 48
Issue : 7
First Page : 2388
Last Page : 2406
Authors : Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T, Brodfuehrer J, Choi C, Barvian MR, Fry DW.
Abstract : A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.
|
Inhibitory concentration was measured by the incorporation of [14C]-thymidine in (human breast carcinoma) MDA-MB-435 cell line
|
None
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.
Year : 2005
Volume : 48
Issue : 7
First Page : 2388
Last Page : 2406
Authors : Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T, Brodfuehrer J, Choi C, Barvian MR, Fry DW.
Abstract : A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.
|
Inhibition of CDK4
|
None
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Radiosynthesis and radiopharmacological evaluation of cyclin-dependent kinase 4 (Cdk4) inhibitors.
Year : 2010
Volume : 45
Issue : 2
First Page : 727
Last Page : 737
Authors : Koehler L, Graf F, Bergmann R, Steinbach J, Pietzsch J, Wuest F.
Abstract : Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two (124)I-labeled Cdk4 inhibitors as potential radiotracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [(124)I]NaI gave radiolabeled Cdk4 inhibitors [(124)I]CKIA and [(124)I]CKIB in radiochemical yields of up to 35%. (124)I-labeled radiotracers [(124)I]CKIA and [(124)I]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [(124)I]CKIA showed substantial uptake in HT-29 and FaDu cells (750-850 %ID/mg protein [(124)I]CKIA and 900-1000 %ID/mg protein [(124)I]CKIB) after 1 h at 37 degrees C. Biodistribution of [(124)I]CKIA and [(124)I]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts.
|
Inhibition of CDK4
|
None
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
Inhibition of CDK6
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: DYRK1A
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: RPS6KA3
|
None
|
794.33
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CLK2
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: PRKCN
|
None
|
398.11
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: DAPK3
|
None
|
125.89
nM
|
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: DAPK3
|
None
|
125.89
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ROCK2
|
None
|
125.89
nM
|
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ROCK2
|
None
|
125.89
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: TAO1
|
None
|
501.19
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CDK5
|
None
|
316.23
nM
|
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CDK5
|
None
|
316.23
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: DYRK1B
|
None
|
100.0
nM
|
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: DYRK1B
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CDK9
|
None
|
398.11
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CLK4
|
None
|
19.95
nM
|
|
PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: CLK4
|
None
|
19.95
nM
|
|
Title : PubChem BioAssay data set
|
SANGER: Inhibition of human NCI-H1770 cell growth in a cell viability assay.
|
Homo sapiens
|
940.55
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H520 cell growth in a cell viability assay.
|
Homo sapiens
|
746.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NKM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
411.89
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ONS-76 cell growth in a cell viability assay.
|
Homo sapiens
|
677.82
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OS-RC-2 cell growth in a cell viability assay.
|
Homo sapiens
|
521.62
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OVCAR-5 cell growth in a cell viability assay.
|
Homo sapiens
|
900.1
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human P12-ICHIKAWA cell growth in a cell viability assay.
|
Homo sapiens
|
96.04
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human PA-1 cell growth in a cell viability assay.
|
Homo sapiens
|
509.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RPMI-8226 cell growth in a cell viability assay.
|
Homo sapiens
|
526.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RS4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
504.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RT-112 cell growth in a cell viability assay.
|
Homo sapiens
|
321.05
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RXF393 cell growth in a cell viability assay.
|
Homo sapiens
|
812.79
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-N-AS cell growth in a cell viability assay.
|
Homo sapiens
|
387.83
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-NEP-1 cell growth in a cell viability assay.
|
Homo sapiens
|
220.02
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW954 cell growth in a cell viability assay.
|
Homo sapiens
|
929.41
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW962 cell growth in a cell viability assay.
|
Homo sapiens
|
808.63
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human T-24 cell growth in a cell viability assay.
|
Homo sapiens
|
778.71
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human 697 cell growth in a cell viability assay.
|
Homo sapiens
|
148.38
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A204 cell growth in a cell viability assay.
|
Homo sapiens
|
633.91
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human AsPC-1 cell growth in a cell viability assay.
|
Homo sapiens
|
252.53
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BE-13 cell growth in a cell viability assay.
|
Homo sapiens
|
444.27
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BHT-101 cell growth in a cell viability assay.
|
Homo sapiens
|
198.25
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BV-173 cell growth in a cell viability assay.
|
Homo sapiens
|
652.48
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAL-27 cell growth in a cell viability assay.
|
Homo sapiens
|
494.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TYK-nu cell growth in a cell viability assay.
|
Homo sapiens
|
998.25
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human U251 cell growth in a cell viability assay.
|
Homo sapiens
|
813.88
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human VA-ES-BJ cell growth in a cell viability assay.
|
Homo sapiens
|
732.27
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAMA-1 cell growth in a cell viability assay.
|
Homo sapiens
|
833.94
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CHP-212 cell growth in a cell viability assay.
|
Homo sapiens
|
593.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COLO-800 cell growth in a cell viability assay.
|
Homo sapiens
|
897.78
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CTB-1 cell growth in a cell viability assay.
|
Homo sapiens
|
405.02
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human D-263MG cell growth in a cell viability assay.
|
Homo sapiens
|
717.12
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EM-2 cell growth in a cell viability assay.
|
Homo sapiens
|
650.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES1 cell growth in a cell viability assay.
|
Homo sapiens
|
256.25
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES3 cell growth in a cell viability assay.
|
Homo sapiens
|
728.93
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES5 cell growth in a cell viability assay.
|
Homo sapiens
|
752.8
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES7 cell growth in a cell viability assay.
|
Homo sapiens
|
273.09
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES8 cell growth in a cell viability assay.
|
Homo sapiens
|
605.21
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-16 cell growth in a cell viability assay.
|
Homo sapiens
|
603.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-3 cell growth in a cell viability assay.
|
Homo sapiens
|
808.76
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EoL-1-cell cell growth in a cell viability assay.
|
Homo sapiens
|
187.26
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human H9 cell growth in a cell viability assay.
|
Homo sapiens
|
495.43
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HAL-01 cell growth in a cell viability assay.
|
Homo sapiens
|
605.67
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HGC-27 cell growth in a cell viability assay.
|
Homo sapiens
|
564.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HH cell growth in a cell viability assay.
|
Homo sapiens
|
599.43
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HL-60 cell growth in a cell viability assay.
|
Homo sapiens
|
340.66
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HO-1-N-1 cell growth in a cell viability assay.
|
Homo sapiens
|
962.81
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HSC-3 cell growth in a cell viability assay.
|
Homo sapiens
|
966.48
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HTC-C3 cell growth in a cell viability assay.
|
Homo sapiens
|
432.95
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human J-RT3-T3-5 cell growth in a cell viability assay.
|
Homo sapiens
|
936.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human JVM-3 cell growth in a cell viability assay.
|
Homo sapiens
|
851.78
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KARPAS-45 cell growth in a cell viability assay.
|
Homo sapiens
|
376.16
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KM-H2 cell growth in a cell viability assay.
|
Homo sapiens
|
695.54
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KOSC-2 cell growth in a cell viability assay.
|
Homo sapiens
|
466.9
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KY821 cell growth in a cell viability assay.
|
Homo sapiens
|
314.1
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LAMA-84 cell growth in a cell viability assay.
|
Homo sapiens
|
258.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LB1047-RCC cell growth in a cell viability assay.
|
Homo sapiens
|
927.56
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MHH-NB-11 cell growth in a cell viability assay.
|
Homo sapiens
|
220.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MHH-PREB-1 cell growth in a cell viability assay.
|
Homo sapiens
|
636.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-16 cell growth in a cell viability assay.
|
Homo sapiens
|
258.49
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-4 cell growth in a cell viability assay.
|
Homo sapiens
|
345.13
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MV-4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
513.85
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human Mewo cell growth in a cell viability assay.
|
Homo sapiens
|
936.6
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB10 cell growth in a cell viability assay.
|
Homo sapiens
|
599.18
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB14 cell growth in a cell viability assay.
|
Homo sapiens
|
483.58
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB69 cell growth in a cell viability assay.
|
Homo sapiens
|
161.8
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NBsusSR cell growth in a cell viability assay.
|
Homo sapiens
|
742.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Inhibition of JAK3 (unknown origin)
|
Homo sapiens
|
63.1
nM
|
|
Journal : J. Med. Chem.
Title : Selectivity data: assessment, predictions, concordance, and implications.
Year : 2013
Volume : 56
Issue : 17
First Page : 6991
Last Page : 7002
Authors : Gao C, Cahya S, Nicolaou CA, Wang J, Watson IA, Cummins DJ, Iversen PW, Vieth M.
Abstract : Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details.
|
Inhibition of CDK9 (unknown origin)
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Selectivity data: assessment, predictions, concordance, and implications.
Year : 2013
Volume : 56
Issue : 17
First Page : 6991
Last Page : 7002
Authors : Gao C, Cahya S, Nicolaou CA, Wang J, Watson IA, Cummins DJ, Iversen PW, Vieth M.
Abstract : Could high-quality in silico predictions in drug discovery eventually replace part or most of experimental testing? To evaluate the agreement of selectivity data from different experimental or predictive sources, we introduce the new metric concordance minimum significant ratio (cMSR). Empowered by cMSR, we find the overall level of agreement between predicted and experimental data to be comparable to that found between experimental results from different sources. However, for molecules that are either highly selective or potent, the concordance between different experimental sources is significantly higher than the concordance between experimental and predicted values. We also show that computational models built from one data set are less predictive for other data sources and highlight the importance of bias correction for assessing selectivity data. Finally, we show that small-molecule target space relationships derived from different data sources and predictive models share overall similarity but can significantly differ in details.
|
Inhibition of CDK6/cyclinD1 (unknown origin)
|
Homo sapiens
|
3.76
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
Year : 2014
Volume : 57
Issue : 3
First Page : 578
Last Page : 599
Authors : Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R, Padgaonkar A, Baker SJ, Reddy EP.
Abstract : The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
|
Inhibition of CDK4/cyclinD1 (unknown origin) using retinoblastoma as substrate after 30 mins by autoradiography in presence of [gamma-32P]ATP
|
Homo sapiens
|
5.36
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
Year : 2014
Volume : 57
Issue : 3
First Page : 578
Last Page : 599
Authors : Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R, Padgaonkar A, Baker SJ, Reddy EP.
Abstract : The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
|
Inhibition of CDK2/cyclinA (unknown origin)
|
Homo sapiens
|
230.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
Year : 2014
Volume : 57
Issue : 3
First Page : 578
Last Page : 599
Authors : Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R, Padgaonkar A, Baker SJ, Reddy EP.
Abstract : The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
|
Inhibition of CDK4/cyclinD1 (unknown origin)
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5).
Year : 2014
Volume : 57
Issue : 3
First Page : 578
Last Page : 599
Authors : Reddy MV, Akula B, Cosenza SC, Athuluridivakar S, Mallireddigari MR, Pallela VR, Billa VK, Subbaiah DR, Bharathi EV, Vasquez-Del Carpio R, Padgaonkar A, Baker SJ, Reddy EP.
Abstract : The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
|
Inhibition of CDK4/cyclin D1 (unknown origin) using Rb as substrate after 60 mins by scintillation counting analysis in presence of [r-33P]ATP
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Antiproliferative activity against Rb-positive human COLO205 cells assessed as incorporation of [3H]thymidine into DNA after 72 hrs by beta-plate counting analysis
|
Homo sapiens
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Antiproliferative activity against human MOLM13 cells harboring FLT3 ITD mutant assessed as incorporation of [3H]thymidine into DNA after 72 hrs by beta-plate counting analysis
|
Homo sapiens
|
96.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Inhibition of CDK4 in human MOLM13 cells assessed as inhibition of Rb phosphorylation at Ser780 after 24 hrs
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Antiproliferative activity against human U937 cells assessed as incorporation of [3H]thymidine into DNA after 72 hrs by beta-plate counting analysis
|
Homo sapiens
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Antiproliferative activity against sorafenib-resistant human MOLM13 cells assessed as incorporation of [3H]thymidine into DNA after 72 hrs by beta-plate counting analysis
|
Homo sapiens
|
96.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Year : 2014
Volume : 57
Issue : 8
First Page : 3430
Last Page : 3449
Authors : Li Z, Wang X, Eksterowicz J, Gribble MW, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, Medina JC.
Abstract : We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.
|
Inhibition of CDK4/cyclin D1 (unknown origin) expressed in baculovirus infected insect cells using GST-fused pRb (792 to 928) as substrate preincubated for 2 mins followed by [gamma-32P]-ATP addition measured after 15 mins by beta plate counting analysis
|
Homo sapiens
|
11.0
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 D2 (unknown origin) expressed in baculovirus infected insect cells using GST-fused pRb (792 to 928) as substrate preincubated for 2 mins followed by [gamma-32P]-ATP addition measured after 15 mins by beta plate counting analysis
|
Homo sapiens
|
9.0
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.
|
Antiproliferative activity against Rb-positive human MDA-MB-435 cells assessed as inhibition of [14C]-thymidine incorporation into DNA preincubated for 24 hrs followed by [14C]-thymidine addition measured after 72 hrs by beta plate counting analysis
|
Homo sapiens
|
160.0
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 (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases.
Year : 2016
Volume : 110
First Page : 291
Last Page : 301
Authors : Vymětalová L, Havlíček L, Šturc A, Skrášková Z, Jorda R, Pospíšil T, Strnad M, Kryštof V.
Abstract : A series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine derivatives was synthesized and evaluated for their cyclin-dependent kinase (CDK) inhibition activity. The most potent compounds contained various hydroxyalkylamines at the 5 position and possessed low nanomolar IC50 values for CDK2 and CDK5. Preliminary profiling of one of the most active compounds on a panel of 50 protein kinases revealed its high selectivity for CDKs. The compounds arrested cells in S and G2/M phases, and induced apoptosis in various cancer cell lines. Significant dephosphorylation of the C-terminus of RNA polymerase II and focal adhesion kinase (FAK), well-established substrates of CDKs, has been found in treated cells. Cleavage of PARP-1, down-regulation of Mcl-1 and activation of caspases correlated well with CDK inhibition and confirmed apoptosis as the primary type of cell death induced in cancer cells treated with the compounds in vitro. A comparison of known purine-based CDK inhibitor CR8 with its pyrazolo[4,3-d]pyrimidine bioisosteres confirmed that the novel compounds are more potent in cellular assays than purines. Therefore, pyrazolo[4,3-d]pyrimidine may emerge as a novel scaffold in medicinal chemistry and as a source of potent CDK inhibitors.
|
Inhibition of CDK9 (unknown origin)
|
Homo sapiens
|
892.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases.
Year : 2016
Volume : 110
First Page : 291
Last Page : 301
Authors : Vymětalová L, Havlíček L, Šturc A, Skrášková Z, Jorda R, Pospíšil T, Strnad M, Kryštof V.
Abstract : A series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine derivatives was synthesized and evaluated for their cyclin-dependent kinase (CDK) inhibition activity. The most potent compounds contained various hydroxyalkylamines at the 5 position and possessed low nanomolar IC50 values for CDK2 and CDK5. Preliminary profiling of one of the most active compounds on a panel of 50 protein kinases revealed its high selectivity for CDKs. The compounds arrested cells in S and G2/M phases, and induced apoptosis in various cancer cell lines. Significant dephosphorylation of the C-terminus of RNA polymerase II and focal adhesion kinase (FAK), well-established substrates of CDKs, has been found in treated cells. Cleavage of PARP-1, down-regulation of Mcl-1 and activation of caspases correlated well with CDK inhibition and confirmed apoptosis as the primary type of cell death induced in cancer cells treated with the compounds in vitro. A comparison of known purine-based CDK inhibitor CR8 with its pyrazolo[4,3-d]pyrimidine bioisosteres confirmed that the novel compounds are more potent in cellular assays than purines. Therefore, pyrazolo[4,3-d]pyrimidine may emerge as a novel scaffold in medicinal chemistry and as a source of potent CDK inhibitors.
|
Inhibition of CDK4/cyclin D1 (unknown origin) expressed in baculovirus infected insect cells using GST-tagged pRB (792 to 928 residues) as substrate preincubated for 2 mins followed by [gamma32P]ATP addition measured after 15 mins by beta counting method
|
Homo sapiens
|
11.0
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 D2 (unknown origin) expressed in baculovirus infected insect cells using GST-tagged pRB (792 to 928 residues) as substrate preincubated for 2 mins followed by [gamma32P]ATP addition measured after 15 mins by beta counting method
|
Homo sapiens
|
15.0
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.
|
Cytotoxicity against human MCF7 cells assessed as reduction in cell viability after 48 hrs by CCK8 assay
|
Homo sapiens
|
240.0
nM
|
|
Journal : Eur J Med Chem
Title : New palbociclib analogues modified at the terminal piperazine ring and their anticancer activities.
Year : 2016
Volume : 122
First Page : 546
Last Page : 556
Authors : Wang P, Huang J, Wang K, Gu Y.
Abstract : A series of new palbociclib analogs by extensive functionalization of the tail piperazine ring with various carbamates and amides have been synthesized. All the palbociclib derivatives were evaluated for their cytotoxic activities against MCF-7 cell line. From the anti-proliferation activity results, two of the tested compounds (compounds 4d and 4e) showed significant cytotoxic effects. And compounds 4d and 4e exhibited potent anticancer activities in MDA-MB-453 and MDA-MB-231 cells. Among these derivatives compound 4e was found to possess cytotoxicity that is better than standard drug palbociclib. Moreover, compound 4e demonstrated robust tumor growth inhibition in vivo model.
|
Inhibition of CDK4 (unknown origin) using histone H1 as substrate after 10 mins in presence of [gamma32P]ATP
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : New palbociclib analogues modified at the terminal piperazine ring and their anticancer activities.
Year : 2016
Volume : 122
First Page : 546
Last Page : 556
Authors : Wang P, Huang J, Wang K, Gu Y.
Abstract : A series of new palbociclib analogs by extensive functionalization of the tail piperazine ring with various carbamates and amides have been synthesized. All the palbociclib derivatives were evaluated for their cytotoxic activities against MCF-7 cell line. From the anti-proliferation activity results, two of the tested compounds (compounds 4d and 4e) showed significant cytotoxic effects. And compounds 4d and 4e exhibited potent anticancer activities in MDA-MB-453 and MDA-MB-231 cells. Among these derivatives compound 4e was found to possess cytotoxicity that is better than standard drug palbociclib. Moreover, compound 4e demonstrated robust tumor growth inhibition in vivo model.
|
Inhibition of CDK6 (unknown origin) using histone H1 as substrate after 10 mins in presence of [gamma32P]ATP
|
Homo sapiens
|
21.0
nM
|
|
Journal : Eur J Med Chem
Title : New palbociclib analogues modified at the terminal piperazine ring and their anticancer activities.
Year : 2016
Volume : 122
First Page : 546
Last Page : 556
Authors : Wang P, Huang J, Wang K, Gu Y.
Abstract : A series of new palbociclib analogs by extensive functionalization of the tail piperazine ring with various carbamates and amides have been synthesized. All the palbociclib derivatives were evaluated for their cytotoxic activities against MCF-7 cell line. From the anti-proliferation activity results, two of the tested compounds (compounds 4d and 4e) showed significant cytotoxic effects. And compounds 4d and 4e exhibited potent anticancer activities in MDA-MB-453 and MDA-MB-231 cells. Among these derivatives compound 4e was found to possess cytotoxicity that is better than standard drug palbociclib. Moreover, compound 4e demonstrated robust tumor growth inhibition in vivo model.
|
Cytotoxicity against human MDA-MB-453 cells assessed as reduction in cell viability after 48 hrs by CCK8 assay
|
Homo sapiens
|
137.0
nM
|
|
Journal : Eur J Med Chem
Title : New palbociclib analogues modified at the terminal piperazine ring and their anticancer activities.
Year : 2016
Volume : 122
First Page : 546
Last Page : 556
Authors : Wang P, Huang J, Wang K, Gu Y.
Abstract : A series of new palbociclib analogs by extensive functionalization of the tail piperazine ring with various carbamates and amides have been synthesized. All the palbociclib derivatives were evaluated for their cytotoxic activities against MCF-7 cell line. From the anti-proliferation activity results, two of the tested compounds (compounds 4d and 4e) showed significant cytotoxic effects. And compounds 4d and 4e exhibited potent anticancer activities in MDA-MB-453 and MDA-MB-231 cells. Among these derivatives compound 4e was found to possess cytotoxicity that is better than standard drug palbociclib. Moreover, compound 4e demonstrated robust tumor growth inhibition in vivo model.
|
Cytotoxicity against human MDA-MB-231 cells assessed as reduction in cell viability after 48 hrs by CCK8 assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : Eur J Med Chem
Title : New palbociclib analogues modified at the terminal piperazine ring and their anticancer activities.
Year : 2016
Volume : 122
First Page : 546
Last Page : 556
Authors : Wang P, Huang J, Wang K, Gu Y.
Abstract : A series of new palbociclib analogs by extensive functionalization of the tail piperazine ring with various carbamates and amides have been synthesized. All the palbociclib derivatives were evaluated for their cytotoxic activities against MCF-7 cell line. From the anti-proliferation activity results, two of the tested compounds (compounds 4d and 4e) showed significant cytotoxic effects. And compounds 4d and 4e exhibited potent anticancer activities in MDA-MB-453 and MDA-MB-231 cells. Among these derivatives compound 4e was found to possess cytotoxicity that is better than standard drug palbociclib. Moreover, compound 4e demonstrated robust tumor growth inhibition in vivo model.
|
Caliper Assay: Selected compounds disclosed herein were tested in CDK4/cyclinD1, CDK6/CycD3 CDK2/CycA and CDK2/cyclinE kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Phosphoacceptor substrate peptide concentration used was 1 μM for all assays and Staurosporine was used as the reference compound for all assays. Specifics of each assay are as described below:CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP concentration: 50 μM; Incubation time: 3 hr.CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP concentration: 100 μM; Incubation time: 1 hr.CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 10 hr.CDK6/CyclinD3: Enzyme concentration: 1 nM; ATP concentration: 300 μM; Incubation time: 3 hr.
|
Homo sapiens
|
10.0
nM
|
|
Title : Transient protection of normal cells during chemotherapy
Year : 2016
|
Caliper Assay: Selected compounds disclosed herein were tested in CDK4/cyclinD1, CDK6/CycD3 CDK2/CycA and CDK2/cyclinE kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Phosphoacceptor substrate peptide concentration used was 1 μM for all assays and Staurosporine was used as the reference compound for all assays. Specifics of each assay are as described below:CDK2/CyclinA: Enzyme concentration: 0.2 nM; ATP concentration: 50 μM; Incubation time: 3 hr.CDK2/CyclinE: Enzyme concentration: 0.28 nM; ATP concentration: 100 μM; Incubation time: 1 hr.CDK4/CyclinD1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 10 hr.CDK6/CyclinD3: Enzyme concentration: 1 nM; ATP concentration: 300 μM; Incubation time: 3 hr.
|
Homo sapiens
|
10.0
nM
|
|
Title : Transient protection of normal cells during chemotherapy
Year : 2016
|
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
|
572.0
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
|
76.0
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
|
276.0
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
|
760.0
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
|
488.0
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
|
208.0
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.
|
Inhibition of CDK4/cyclin D1 (unknown origin) in presence of [gamma-33P]-ATP by KINOMEscan assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : J Med Chem
Title : Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation.
Year : 2017
Volume : 60
Issue : 5
First Page : 1892
Last Page : 1915
Authors : Tadesse S, Yu M, Mekonnen LB, Lam F, Islam S, Tomusange K, Rahaman MH, Noll B, Basnet SK, Teo T, Albrecht H, Milne R, Wang S.
Abstract : Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
|
Inhibition of CDK6/cyclin D3 (unknown origin) in presence of [gamma-33P]-ATP by KINOMEscan assay
|
Homo sapiens
|
27.0
nM
|
|
Journal : J Med Chem
Title : Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation.
Year : 2017
Volume : 60
Issue : 5
First Page : 1892
Last Page : 1915
Authors : Tadesse S, Yu M, Mekonnen LB, Lam F, Islam S, Tomusange K, Rahaman MH, Noll B, Basnet SK, Teo T, Albrecht H, Milne R, Wang S.
Abstract : Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
|
Inhibition of CDK9/cyclin T1 (unknown origin) in presence of [gamma-33P]-ATP by KINOMEscan assay
|
Homo sapiens
|
364.0
nM
|
|
Journal : J Med Chem
Title : Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation.
Year : 2017
Volume : 60
Issue : 5
First Page : 1892
Last Page : 1915
Authors : Tadesse S, Yu M, Mekonnen LB, Lam F, Islam S, Tomusange K, Rahaman MH, Noll B, Basnet SK, Teo T, Albrecht H, Milne R, Wang S.
Abstract : Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
|
Inhibition of CDK6/Cyclin-D3 (unknown origin) using histoneH1 as substrate after 90 mins by ADP-Glo assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : Eur J Med Chem
Title : A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy.
Year : 2018
Volume : 144
First Page : 1
Last Page : 28
Authors : Yin L, Li H, Liu W, Yao Z, Cheng Z, Zhang H, Zou H.
Abstract : Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p < 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM.
|
Inhibition of CDK4 (unknown origin)
|
Homo sapiens
|
11.0
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 CDK6 (unknown origin)
|
Homo sapiens
|
16.0
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 GST-tagged CDK4/cyclin D1 (unknown origin) expressed in Baculovirus infected Sf9 cells using RPPTLSPIPHIPR peptide as substrate in presence of [gamma-33P]-ATP by radiometric filter binding assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : How Selective Are Pharmacological Inhibitors of Cell-Cycle-Regulating Cyclin-Dependent Kinases?
Year : 2018
Volume : 61
Issue : 20
First Page : 9105
Last Page : 9120
Authors : Jorda R, Hendrychová D, Voller J, Řezníčková E, Gucký T, Kryštof V.
Abstract : Cyclin-dependent kinases (CDKs) are an important and emerging class of drug targets for which many small-molecule inhibitors have been developed. However, there is often insufficient data available on the selectivity of CDK inhibitors (CDKi) to attribute the effects on the presumed target CDK to these inhibitors. Here, we highlight discrepancies between the kinase selectivity of CDKi and the phenotype exhibited; we evaluated 31 CDKi (claimed to target CDK1-4) for activity toward CDKs 1, 2, 4, 5, 7, 9 and for effects on the cell cycle. Our results suggest that most CDKi should be reclassified as pan-selective and should not be used as a tool. In addition, some compounds did not even inhibit CDKs as their primary cellular targets; for example, NU6140 showed potent inhibition of Aurora kinases. We also established an online database of commercially available CDKi for critical evaluation of their utility as molecular probes. Our results should help researchers select the most relevant chemical tools for their specific applications.
|
Antiproliferative activity against human MM1S cells after 84 hrs by CCK8 assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J Med Chem
Title : Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.
Year : 2019
Volume : 62
Issue : 16
First Page : 7575
Last Page : 7582
Authors : Su S, Yang Z, Gao H, Yang H, Zhu S, An Z, Wang J, Li Q, Chandarlapaty S, Deng H, Wu W, Rao Y.
Abstract : A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.
|
Antiproliferative activity against human Mino cells after 84 hrs by CCK8 assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : J Med Chem
Title : Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders.
Year : 2019
Volume : 62
Issue : 16
First Page : 7575
Last Page : 7582
Authors : Su S, Yang Z, Gao H, Yang H, Zhu S, An Z, Wang J, Li Q, Chandarlapaty S, Deng H, Wu W, Rao Y.
Abstract : A focused PROTAC library hijacking cancer therapeutic target CDK6 was developed. A design principle as "match/mismatch" was proposed for understanding the degradation profile differences in these PROTACs. Notably, potent PROTACs with specific and remarkable CDK6 degradation potential were generated by linking CDK6 inhibitor palbociclib and E3 ligase CRBN recruiter pomalidomide. The PROTAC strongly inhibited proliferation of hematopoietic cancer cells including multiple myeloma and robustly degraded copy-amplified/mutated forms of CDK6, indicating future potential clinical applications.
|
Inhibition of CDK4 (unknown origin)
|
Homo sapiens
|
9.0
nM
|
|
Journal : Eur J Med Chem
Title : Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib.
Year : 2019
Volume : 172
First Page : 143
Last Page : 153
Authors : Poratti M, Marzaro G.
Abstract : The role of cyclin-dependent kinases (CDKs) in regulating the transition of cell cycle steps makes this class of enzymes a suitable target for cancer therapy. Three different generations of CDKs inhibitors have been developed so far. Third-generation compounds (i.e. selective CDK4/6 inhibitors) are the most promising ones, due to their limited toxicity and high in vivo activity. To date, three compounds have entered the therapy, namely Palbociclib, Ribociclib and Abemaciclib. Herein we review the medicinal chemistry aspects of these drugs, with some references to very similar analogues that have been published.
|
Inhibition of CDK6 (unknown origin)
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : Third-generation CDK inhibitors: A review on the synthesis and binding modes of Palbociclib, Ribociclib and Abemaciclib.
Year : 2019
Volume : 172
First Page : 143
Last Page : 153
Authors : Poratti M, Marzaro G.
Abstract : The role of cyclin-dependent kinases (CDKs) in regulating the transition of cell cycle steps makes this class of enzymes a suitable target for cancer therapy. Three different generations of CDKs inhibitors have been developed so far. Third-generation compounds (i.e. selective CDK4/6 inhibitors) are the most promising ones, due to their limited toxicity and high in vivo activity. To date, three compounds have entered the therapy, namely Palbociclib, Ribociclib and Abemaciclib. Herein we review the medicinal chemistry aspects of these drugs, with some references to very similar analogues that have been published.
|
Inhibition of human full length N-terminal GST-tagged CDK6 (1 to 326 end residues)/CyclinD3 (1 to 292 end residues) expressed in baculovirus expression system at 1 uM using FAM-labelled peptide as substrate preincubated for 10 mins followed by substrate addition measured after 1 hr relative to control
|
Homo sapiens
|
97.3
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivative as potent antitumor agents.
Year : 2019
Volume : 163
First Page : 690
Last Page : 709
Authors : Hou Y, Zhu L, Li Z, Shen Q, Xu Q, Li W, Liu Y, Gong P.
Abstract : To develop novel therapeutic agents with anticancer activities, two series of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridinone derivatives were designed and synthesized. All compounds were tested for anti-proliferative activities against five cancer cell lines. The structure-activity relationships (SARs) studies were conducted through the variation in two regions, the moiety of A ring and the terminal aniline B on pteridinone core. 1-Methyl-1,2,4-triazole derivative L7 with 2,6-dimethylpiperazine showed the most potent antiproliferative activity against A549, PC-3, HCT116, MCF-7 and MDA-MB-231 cell lines with IC50 values of 0.16 μM, 0.30 μM, 0.51 μM, 0.30 μM, and 0.70 μM, respectively. Combined with the results of the molecular docking and enzymatic studies, the PLK1 was very likely to be one of the drug targets of compound L7. Furthermore, to clarify the anticancer mechanism of compound L7, further explorations in the bioactivity were conducted. The results showed that compound L7 obviously inhibited proliferation of A549 cell lines, induced a great decrease in mitochondrial membrane potential leading to apoptosis of cancer cells, suppressed the migration of tumor cells, and arrested G1 phase of A549 cells.
|
Inhibition of recombinant human N-terminal GST-tagged CDK4 (S4 to E303 residues)/Cyclin D1 (Q4 to I295 residues) expressed in sf9 cells at 10 uM using RBCTF as substrate measured after 1 hr by ADP-glo luminescence assay relative to control
|
Homo sapiens
|
95.0
%
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of human full length N-terminal GST-fused CDK2 (M1 to L298 residues)/human full length Cyclin-A2 (M1 to L432 residues) expressed in Sf9 cells at 10 uM using histone H1 as substrate measured after 1 hr by ADP-glo luminescence assay relative to control
|
Homo sapiens
|
42.0
%
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of recombinant human N-terminal GST/His6-tagged CDK1 (M1 to M297 residues)/CyclinB1 (M1 to V433 residues) expressed in Sf9 insect cells at 10 uM using RBCTF as substrate measured after 1 hr by ADP-glo luminescence assay relative to control
|
Homo sapiens
|
5.0
%
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of N-terminal GST-HIS6 fusion protein tagged human full length CDK9 (M1 to F372 residues)/N-terminal HIS6-fused human Cyclin-T1 (M1 to K726 residues) expressed in Sf9 cells at 10 uM using RBCTF as substrate measured after 1 hr by ADP-glo luminescence assay relative to control
|
Homo sapiens
|
-4.0
%
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of CDK6/cyclin D1 (unknown origin) at 10 uM using RBER-CHKtide as substrate measured after 1 hr by ADP-glo luminescence assay relative to control
|
Homo sapiens
|
-97.0
%
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of recombinant human N-terminal GST-tagged CDK4 (S4 to E303 residues)/Cyclin D1 (Q4 to I295 residues) expressed in sf9 cells using RBCTF as substrate measured after 1 hr by ADP-glo luminescence assay
|
Homo sapiens
|
13.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of CDK6/cyclin D1 (unknown origin) using RBER-CHKtide as substrate measured after 1 hr by ADP-glo luminescence assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Growth inhibition of human A549 cells measured after 72 hrs by propidium iodide staining based fluorescence assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Growth inhibition of human T47D cells measured after 72 hrs by propidium iodide staining based fluorescence assay
|
Homo sapiens
|
350.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of CDK4/cyclin D1 (unknown origin)
|
Homo sapiens
|
11.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
Inhibition of CDK6/cyclin D1 (unknown origin)
|
Homo sapiens
|
16.0
nM
|
|
Journal : Eur J Med Chem
Title : Cink4T, a quinazolinone-based dual inhibitor of Cdk4 and tubulin polymerization, identified via ligand-based virtual screening, for efficient anticancer therapy.
Year : 2019
Volume : 165
First Page : 115
Last Page : 132
Authors : Sonawane V, Mohd Siddique MU, Jadav SS, Sinha BN, Jayaprakash V, Chaudhuri B.
Abstract : Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G<sub>0</sub>/G<sub>1</sub> phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC<sub>50</sub> values of 6.2 and 10 μM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC<sub>50</sub> value for Cdk4 inhibition is 0.47 μM and >50 μM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC<sub>50</sub> of 0.6 μM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G<sub>0</sub>/G<sub>1</sub> and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.33
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.01
%
|
|
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.
|
Inhibition of recombinant human full-length N-terminal His-tagged CDK6/cyclinD3 expressed in baculovirus infected Sf9 insect cells using histone H1 as substrate measured after 60 mins by ADP-glo assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity.
Year : 2020
Volume : 63
Issue : 6
First Page : 3327
Last Page : 3347
Authors : Wang Y, Chen X, Yan Y, Zhu X, Liu M, Liu X.
Abstract : Cyclin-dependent kinases (CDKs) are promising therapeutic targets for cancer therapy. Herein, we describe our efforts toward the discovery of a series of 5-chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4-diamine derivatives as dual CDK6 and 9 inhibitors. Intensive structural modifications lead to the identification of compound 66 as the most active dual CDK6/9 inhibitor with balancing potency against these two targets and good selectivity over CDK2. Further biological studies revealed that compound 66 was directly bound to CDK6/9, resulting in suppression of their downstream signaling pathway and inhibition of cell proliferation by blocking cell cycle progression and inducing cellular apoptosis. More importantly, compound 66 significantly inhibited tumor growth in a xenograft mouse model with no obvious toxicity, indicating the promising therapeutic potential of CDK6/9 dual inhibitors for cancer treatment. Therefore, the above results are of great importance in the development of dual CDK6/9 inhibitors for cancer therapy.
|
Inhibition of human CDK4/cyclin-D1 using RB protein as substrate by [gamma-33P]-ATP assay
|
Homo sapiens
|
31.62
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
Year : 2020
Volume : 30
Issue : 9
First Page : 127106
Last Page : 127106
Authors : Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB.
Abstract : Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.
|
Inhibition of human CDK6/cyclin-D3 using RB protein as substrate by [gamma-33P]-ATP assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
Year : 2020
Volume : 30
Issue : 9
First Page : 127106
Last Page : 127106
Authors : Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB.
Abstract : Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.
|
Inhibition of human CDK4/cyclin-D1 (unknown origin)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
Year : 2020
Volume : 30
Issue : 9
First Page : 127106
Last Page : 127106
Authors : Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB.
Abstract : Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.
|
Inhibition of human CDK6/cyclin-D2 (unknown origin)
|
Homo sapiens
|
15.85
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs.
Year : 2020
Volume : 30
Issue : 9
First Page : 127106
Last Page : 127106
Authors : Anderson NA, Cryan J, Ahmed A, Dai H, McGonagle GA, Rozier C, Benowitz AB.
Abstract : Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin-proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder.
|
Inhibition of CDK4 (unknown origin)
|
Homo sapiens
|
8.2
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 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
|
230.0
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 human CDK4/cyclin D (unknown origin) using FAM-labeled peptide and ATP as substrate preincubated for 10 mins followed by substrate addition by mobility shift assay
|
Homo sapiens
|
11.0
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 recombinant human full-length N-terminal GST-fused CDK4 (1 to 303 residues)/GST-tagged CyclinD3 (1 to 292 residues) expressed in baculovirus expression system using ULight-elF4E-binding protein 1 peptide as substrate measured after 30 mins by LANCE assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors.
Year : 2020
Volume : 193
First Page : 112239
Last Page : 112239
Authors : Shi C,Wang Q,Liao X,Ge H,Huo G,Zhang L,Chen N,Zhai X,Hong Y,Wang L,Wang Z,Shi W,Mao Y,Yu J,Ke Y,Xia G
Abstract : CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
|
Inhibition of human full-length N-terminal GST tagged CDK6 (1 to 326 residues)/GST-tagged cyclinD3 (1 to 292 residues) expressed in baculovirus expression system using ULight-elF4E-binding protein 1 peptide as substrate measured after 30 mins by LANCE assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors.
Year : 2020
Volume : 193
First Page : 112239
Last Page : 112239
Authors : Shi C,Wang Q,Liao X,Ge H,Huo G,Zhang L,Chen N,Zhai X,Hong Y,Wang L,Wang Z,Shi W,Mao Y,Yu J,Ke Y,Xia G
Abstract : CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
|
Antiproliferative activity against human COLO 205 cells assessed as cell growth inhibition measured after 4 to 6 days by celltiter-glo luminescent cell viability assay
|
Homo sapiens
|
300.6
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors.
Year : 2020
Volume : 193
First Page : 112239
Last Page : 112239
Authors : Shi C,Wang Q,Liao X,Ge H,Huo G,Zhang L,Chen N,Zhai X,Hong Y,Wang L,Wang Z,Shi W,Mao Y,Yu J,Ke Y,Xia G
Abstract : CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
|
Antiproliferative activity against human U-87 MG cells assessed as cell growth inhibition measured after 4 to 6 days by celltiter-glo luminescent cell viability assay
|
Homo sapiens
|
345.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of a novel series of imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin derivatives as potent cyclin-dependent kinase 4/6 inhibitors.
Year : 2020
Volume : 193
First Page : 112239
Last Page : 112239
Authors : Shi C,Wang Q,Liao X,Ge H,Huo G,Zhang L,Chen N,Zhai X,Hong Y,Wang L,Wang Z,Shi W,Mao Y,Yu J,Ke Y,Xia G
Abstract : CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
|
Antiproliferative activity against human MCF7 cells assessed as reduction in cell viability after 72 hrs by MTT assay
|
Homo sapiens
|
340.0
nM
|
|
|
Inhibition of CDK4/Cyclin D1 (unknown origin) at 200 nM using ATP by mobility shift assay
|
Homo sapiens
|
98.17
%
|
|
|
Inhibition of CDK4/Cyclin D1 (unknown origin) at 20 nM using ATP by mobility shift assay
|
Homo sapiens
|
70.94
%
|
|
|
Inhibition of CDK6/Cyclin D3 (unknown origin) at 200 nM using ATP by mobility shift assay
|
Homo sapiens
|
104.7
%
|
|
|
Inhibition of CDK6/Cyclin D3 (unknown origin) at 20 nM using ATP by mobility shift assay
|
Homo sapiens
|
94.1
%
|
|
|
Inhibition of CDK6/Cyclin D3 (unknown origin) by mobility shift assay
|
Homo sapiens
|
10.27
nM
|
|
|
Inhibition of CDK4/Cyclin D3 (unknown origin) by mobility shift assay
|
Homo sapiens
|
3.44
nM
|
|
|
Inhibition of CDK6/Cyclin D1 (unknown origin) using ULight-MBP peptide substrate in presence of ATP by TR-FRET assay
|
Homo sapiens
|
18.0
nM
|
|
