2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.

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Wang S, Meades C, Wood G, Osnowski A, Anderson S, Yuill R, Thomas M, Mezna M, Jackson W, Midgley C, Griffiths G, Fleming I, Green S, McNae I, Wu SY, McInnes C, Zheleva D, Walkinshaw MD, Fischer PM

2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.

J Med Chem. 2004 Mar 25;47(7):1662-75.

PubMed ID

15027857 [ View in PubMed

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Abstract

Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-[4-(2,4-Dimethyl-Thiazol-5-Yl)-Pyrimidin-2-Ylamino]-Phenol	Cyclin-dependent kinase 2	Ki (nM)	60	7.4	30	Details
4-(2,4-Dimethyl-1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)phenyl]-2-pyrimidinamine	Cyclin-dependent kinase 2	Ki (nM)	290	7.4	30	Details
4-(2,4-Dimethyl-Thiazol-5-Yl)-Pyrimidin-2-Ylamine	Cyclin-dependent kinase 2	Ki (nM)	6500	7.4	30	Details