1PXP

HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR N-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-N',N'-dimethyl-benzene-1,4-diamine

Summary for 1PXP

• Entry DOI: 10.2210/pdb1pxp/pdb
• Related: 1AQ1 1B39 1CKP 1DI8 1DM2 1E1V 1E1X 1E9H 1FIN 1FVT 1FVV 1G5S 1GIH 1GII 1GIJ 1GZ8 1HCK 1HCL 1JSV 1JVP 1KE5 1KE6 1KE7 1KE8 1KE9 1PXM 1PXN 1PXO
• Descriptor: Cell division protein kinase 2, N-[4-(2,4-DIMETHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-N',N'-DIMETHYL-BENZENE-1,4-DIAMINE (3 entities in total)
• Functional Keywords: protein kinase, cell cycle, phosphorylation, cell division, mitosis, inhibition, transferase, serine/threonine-protein kinase, atp-binding, 3d-structure.
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34301.92

Authors

Wang, S.,Meades, C.,Wood, G.,Osnowski, A.,Anderson, S.,Yuill, R.,Thomas, M.,Mezna, M.,Jackson, W.,Midgley, C.,Griffiths, G.,McNae, I.,Wu, S.Y.,McInnes, C.,Zheleva, D.,Walkinshaw, M.D.,Fischer, P.M. (deposition date: 2003-07-04, release date: 2004-04-13, Last modification date: 2023-08-16)

Primary citation

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, S.Y.,McInnes, C.,Zheleva, D.,Walkinshaw, M.D.,Fischer, P.M.
2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
J.Med.Chem., 47:1662-1675, 2004

PubMed 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.

PubMed: 15027857
DOI: 10.1021/jm0309957

Experimental method

X-RAY DIFFRACTION (2.3 Å)