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.
|DOI (Digital Object Identifier) Link:||http://dx.doi.org/10.1021/jm0309957|
|Google Scholar:||Look up in Google Scholar|
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|
|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)|
|Depositing User:||Carol Midgley|
|Date Deposited:||12 Jun 2006|
|Last Modified:||14 Jan 2016 15:47|
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