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spinqualitylabelsall models 1pxm, resolution 2.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenol

Overview

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.

About this Structure

1PXM is a Single protein structure of sequence from Homo sapiens with CK5 as ligand. Full crystallographic information is available from OCA.

Reference

2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity., 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, J Med Chem. 2004 Mar 25;47(7):1662-75. PMID:15027857

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