Coxon, CR (2016) Cyclin-Dependent Kinase (CDK) Inhibitors; Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines. Journal of Medicinal Chemistry, 60 (5). pp. 1746-1767. ISSN 0022-2623

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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 favour 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 towards CDK2 (IC50 0.044 μM), but was ~ 2000-fold less active towards 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.

Item Type:	Article
Uncontrolled Keywords:	0304 Medicinal And Biomolecular Chemistry, 1115 Pharmacology And Pharmaceutical Sciences, 0305 Organic Chemistry
Subjects:	Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	American Chemical Society
Related URLs:	Author
Date Deposited:	27 Jan 2017 09:55
Last Modified:	04 Sep 2021 12:06
DOI or ID number:	10.1021/acs.jmedchem.6b01254
URI:	https://researchonline.ljmu.ac.uk/id/eprint/5242

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