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2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity

Wang, Shudong; Meades, Christopher; Wood, Gavin; Osnowski, Andrew; Anderson, Sian; Yuill, Rhoda; Thomas, Mark; Mezna, Mokdad; Jackson, Wayne; Midgley, Carol; Griffiths, Gary; Fleming, Ian; Green, Simon; McNae, Ian; Wu, Su-Ying; McInnes, Campbell; Zheleva, Daniella; Walkinshaw, Malcolm D. and Fischer, Peter M. (2004). 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK Inhibitors: Synthesis, SAR Analysis, X-ray Crystallography, and Biological Activity. Journal of Medicinal Chemistry, 47(7) pp. 1662–1675.

URL: http://pubs.acs.org/cgi-bin/article.cgi/jmcmar/200...
DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1021/jm0309957
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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.

Item Type: Journal Article
ISSN: 1520-4804
Extra Information: Some of the symbols may not have transferred correctly into this bibliographic record and/or abstract.
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 2304
Depositing User: Carol Midgley
Date Deposited: 12 Jun 2006
Last Modified: 07 Mar 2014 13:30
URI: http://oro.open.ac.uk/id/eprint/2304
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