Hole, A., Baumli, S., Shao, H., Shi, S., Huang, S., Pepper, Christopher John, Fischer, P., Wang, S., Endicott, J. and Noble, M. 2013. Comparative structural and functional studies of 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. Journal of Medicinal Chemistry 56 (3) , pp. 660-670. 10.1021/jm301495v |
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.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Subjects: | R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine |
Uncontrolled Keywords: | Cyclin-Dependent Kinase 9; Humans; Models, Molecular; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship |
Publisher: | American Chemical Society |
ISSN: | 0022-2623 |
Last Modified: | 04 Jun 2017 08:18 |
URI: | https://orca.cardiff.ac.uk/id/eprint/75597 |
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