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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

Lookup NU author(s): Dr Alison Hole, Dr Sonja Baumli, Professor Jane Endicott, Professor Martin NobleORCiD



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-dichlorobenzimida-zone-1-beta-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.

Publication metadata

Author(s): Hole AJ, Baumli S, Shao H, Shi SH, Huang SL, Pepper C, Fischer PM, Wang SD, Endicott JA, Noble ME

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2013

Volume: 56

Issue: 3

Pages: 660-670

Print publication date: 20/12/2012

Date deposited: 24/06/2013

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm301495v


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Funder referenceFunder name
083113/Z/07/AWellcome Trust
C21568/A12474Cancer Research UK
C21568/A8988Cancer Research UK