Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Christopher R. Coxon, Elizabeth Anscombe, Suzannah J. Harnor, Mathew P. Martin, Benoit Carbain, Bernard T. Golding, Ian R. Hardcastle, Lisa K. Harlow, Svitlana Korolchuk, Christopher J. Matheson, David R. Newell, Martin E. M. Noble, Mangaleswaran Sivaprakasam, Susan J. Tudhope, David M. Turner, Lan Z. Wang, Stephen R. Wedge, Christopher Wong, Roger J. Griffin, Jane A. EndicottCéline Cano

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51 Citations (Scopus)
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Abstract

Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1′-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

Original languageEnglish
Pages (from-to)1746-1767
Number of pages22
JournalJournal of Medicinal Chemistry
Volume60
Issue number5
Early online date14 Feb 2017
DOIs
Publication statusPublished - 9 Mar 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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