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Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity.

Abstract
Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.
AuthorsAlison J Hole, Sonja Baumli, Hao Shao, Shenhua Shi, Shiliang Huang, Chris Pepper, Peter M Fischer, Shudong Wang, Jane A Endicott, Martin E Noble
JournalJournal of medicinal chemistry (J Med Chem) Vol. 56 Issue 3 Pg. 660-70 (Feb 14 2013) ISSN: 1520-4804 [Electronic] United States
PMID23252711 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Protein Kinase Inhibitors
  • Pyrimidines
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9
Topics
  • Cyclin-Dependent Kinase 9 (antagonists & inhibitors)
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors (chemistry, pharmacology)
  • Pyrimidines (chemistry, pharmacology)
  • Structure-Activity Relationship

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