Target Validation Information
Target ID T70176
Target Name Cell division protein kinase 2
Target Type
Clinical Trial
Drug Potency against Target SNS-032 Drug Info Ki = 38 nM
SCH 727965 Drug Info Ki = 1 nM [553063]
AG-024322 Drug Info IC50 = 1~3 nM [537564]
AT7519 Drug Info IC50 = 10 nM [552960]
6-(Cyclohex-3-enylmethoxy)-9H-purin-2-ylamine Drug Info IC50 = 13000 nM [526389]
(2'Z,3'E)-5-Nitro-5'-methoxy-indirubin-3'-oxime Drug Info IC50 = 2950 nM [530823]
MERIOLIN 5 Drug Info IC50 = 3 nM [529275]
MERIOLIN 3 Drug Info IC50 = 11 nM [529275]
MERIOLIN 1 Drug Info IC50 = 90 nM [529275]
MERIOLIN 2 Drug Info IC50 = 18 nM [529275]
Flavopiridol Drug Info IC50 = 60 nM [552961]
NU-6086 Drug Info IC50 = 1000 nM [530065]
Seliciclib Drug Info IC50 = 200 nM [552773]
R547 Drug Info IC50 = 1~3 nM [537564]
N-(4-amino-5-cyano-6-phenylpyridin-2-yl)acetamide Drug Info Ki = 1300 nM [528237]
NU-6094 Drug Info IC50 = 2300 nM [530065]
BOHEMINE Drug Info IC50 = 800 nM [525825]
3-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol Drug Info IC50 = 6000 nM [528490]
PYRAZOLOPYRIDAZINE 1 Drug Info Ki = 2 nM [527192]
R-roscovitine Drug Info Ki = 100 nM [553081]
PD-0183812 Drug Info IC50 = 165 nM [525924]
NU-6102 Drug Info IC50 = 8.1 nM [528404]
NU-6027 Drug Info IC50 = 2200 nM [526489]
MERIOLIN 8 Drug Info IC50 = 1800 nM [529275]
MERIOLIN 6 Drug Info IC50 = 5.1 nM [529275]
PURVALANOLA Drug Info IC50 = 30 nM [529039]
2-((3,5-diamino-1H-pyrazol-4-yl)diazenyl)phenol Drug Info IC50 = 2500 nM [528490]
(2'Z,3'E)-5-Fluoro-5'-methoxy-indirubin-3'-oxime Drug Info IC50 = 4120 nM [530823]
5-nitroindirubin-3'-oxime Drug Info IC50 = 7.35 nM [530823]
JNJ-7706621 Drug Info IC50 = 2 nM [528188]
RESCOVITINE Drug Info IC50 = 500 nM [530612]
GW-8510 Drug Info IC50 = 10 nM [526991]
PYRAZOLOPYRIDAZINE 2 Drug Info Ki = 50 nM [527192]
4-(7-Butyl-5H-pyrrolo[2,3-b]pyrazin-6-yl)-phenol Drug Info IC50 = 400 nM [526504]
MERIOLIN 4 Drug Info IC50 = 7 nM [529275]
4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info IC50 = 3500 nM [528490]
Benzyl-(9-isopropyl-9H-purin-6-yl)-amine Drug Info IC50 = 4500 nM [525825]
ZK 304709 Drug Info Ki = 4 nM [552625]
NU-2058 Drug Info Ki = 1200 nM [528372]
Action against Disease Model Flavopiridol Induced G1-S phase and G2-M phase arrest and apoptosis at 200-300 nM concentrations in many tumor cell types. Significant clinical activity in refractory CLL; clinical studies ongoing to determine efficacy of combination with anti-neoplastic agents. [537564] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Loss of Cdk2 alters the regulation of several proteins that are known to regulate S-phase progression, but also control mitotic entry, including Cdc25A, Chk1, Cdc6 and ATRIP. Cdk2 shows a unique role in facilitating robust DNA damage checkpoint control by the ATR-Chk1-Cdc25A pathway, and appears to promote the formation of active ATR complexes in at least two ways: via the phosphorylation of ATRIP and by the stabilization of Cdc6. In conclusion, Cdk2 uniquely controls the G2/M checkpoint that prevents cells with damaged DNA from initiating mitosis. These findings demonstrate that Cdk2 maintains a balance of S-phase regulatory proteins and thereby coordinates subsequent p53-independent G2/M checkpoint activation.
References
Ref 553063Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 552960Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds. Nat Rev Drug Discov. 2009 Jul;8(7):567-78. doi: 10.1038/nrd2876.
Ref 526389J Med Chem. 2002 Aug 1;45(16):3381-93.Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.
Ref 530823J Med Chem. 2010 May 13;53(9):3696-706.5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 552961End of the line for cannabinoid receptor 1 as an anti-obesity target? An opinion. Nat Rev Drug Discov. 2009 Jul;8(7):594. doi: 10.1038/nrd2775-c1.
Ref 530065J Med Chem. 2009 May 14;52(9):2854-62.Halogen bonding--a novel interaction for rational drug design?.
Ref 552773A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008 Jan;26(1):127-32. doi: 10.1038/nbt1358.
Ref 537564Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
Ref 528237J Med Chem. 2006 Jun 15;49(12):3563-80.Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity.
Ref 530065J Med Chem. 2009 May 14;52(9):2854-62.Halogen bonding--a novel interaction for rational drug design?.
Ref 525825J Med Chem. 2000 Jun 29;43(13):2506-13.Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 527192J Med Chem. 2004 Sep 9;47(19):4716-30.N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
Ref 553081A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration. J Med Chem. 2010 Dec 23;53(24):8508-22. doi: 10.1021/jm100732t. Epub 2010 Nov 16.
Ref 525924J Med Chem. 2000 Nov 30;43(24):4606-16.Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.
Ref 528404J Med Chem. 2006 Sep 7;49(18):5470-7.Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity.
Ref 526489Bioorg Med Chem Lett. 2003 Jan 20;13(2):217-22.4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 530823J Med Chem. 2010 May 13;53(9):3696-706.5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
Ref 530823J Med Chem. 2010 May 13;53(9):3696-706.5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
Ref 528188Bioorg Med Chem Lett. 2006 Jul 15;16(14):3639-41. Epub 2006 May 6.Synthesis and evaluation of N-acyl sulfonamides as potential prodrugs of cyclin-dependent kinase inhibitor JNJ-7706621.
Ref 530612Eur J Med Chem. 2010 Mar;45(3):1158-66. Epub 2009 Dec 21.Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors.
Ref 526991Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles.
Ref 527192J Med Chem. 2004 Sep 9;47(19):4716-30.N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy.
Ref 526504J Med Chem. 2003 Jan 16;46(2):222-36.Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.
Ref 529275J Med Chem. 2008 Feb 28;51(4):737-51. Epub 2008 Jan 31.Meriolins (3-(pyrimidin-4-yl)-7-azaindoles): synthesis, kinase inhibitory activity, cellular effects, and structure of a CDK2/cyclin A/meriolincomplex.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 525825J Med Chem. 2000 Jun 29;43(13):2506-13.Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2.
Ref 552625Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed Pharmacother. 2006 Jul;60(6):269-72. Epub 2006 Jun 23.
Ref 528372J Med Chem. 2006 Aug 24;49(17):5141-53.Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations.

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