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

Shudong Wang, Christopher Meades, Gavin Wood, Andrew Osnowski, Sian Anderson, Rhoda Yuill, Mark Thomas, Mokdad Mezna, Wayne Jackson, Carol Midgley, Gary Griffiths, Ian Neil Fleming, Simon R Green, Iain McNae, Su-Ying Wu, Campbell McInnes, Daniella Zheleva, Malcolm D Walkinshaw, Peter M Fischer

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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.
Original languageEnglish
Pages (from-to)1662-1675
Number of pages14
JournalJournal of Medicinal Chemistry
Volume47
Issue number7
DOIs
Publication statusPublished - 25 Mar 2004

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Keywords

  • aniline compounds
  • antineoplastic agents
  • CDC2-CDC28 kinases
  • cell cycle
  • tumor cell line
  • X-ray crystallography
  • cyclin-dependent kinase 2
  • cyclin-dependent kinase 9
  • humans
  • molecular structure
  • pyrimidines
  • structure-activity relationship
  • thiazoles

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