Comparative Structural and Functional Studies of 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 Inhibitors Suggest the Basis for Isotype Selectivity

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• 作者：Alison J. Hole ; Sonja Baumli ; Hao Shao ; Shenhua Shi ; Shiliang Huang ; Chris Pepper ; Peter M. Fischer ; Shudong Wang ; Jane A. Endicott ; Martin E. Noble
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：660-670
• 全文大小：553K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

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-尾-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.