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Cyclin-Dependent Kinase (CDK) Inhibitors; Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

DOI: 10.1021/acs.jmedchem.6b01254 DOI Help

Authors: Christopher R Coxon (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Elizabeth Anscombe (University of Oxford) , Suzannah Jane Harnor (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Mathew P. Martin (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Benoit Jean-pierre Carbain (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Bernard Thomas Golding (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Ian Robert Hardcastle (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Lisa K Harlow (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Svitlana Korolchuk (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Christopher J. Matheson (Newcastle Cancer Centre, Northern Institute for Cancer Research) , David R. Newell (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Martin E. M. Noble (University of Oxford) , Mangaleswaran Sivaprakasam (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Susan J. Tudhope (Newcastle Cancer Centre, Northern Institute for Cancer Research) , David M. Turner (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Lan-zhen Wang (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Stephen R Wedge (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Christopher Wong (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Roger John Griffin (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Jane A. Endicott (Newcastle Cancer Centre, Northern Institute for Cancer Research) , Celine Cano (Newcastle Cancer Centre, Northern Institute for Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2016
Diamond Proposal Number(s): 13587

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.

Journal Keywords: CDK; cyclin; X-ray crystallography; structure-aided inhibitor design; protein kinase

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)