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8-Substituted O6-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode

DOI: 10.1021/jm401555v DOI Help
PMID: 24304238 PMID Help

Authors: Benoit Carbain (University of Oxford) , David J. Paterson (University of Oxford) , Elizabeth Anscombe (University of Oxford) , Allyson J. Campbell (Newcastle University) , Celine Cano (Newcastle University) , Aude Echalier (University of Oxford) , Jane A. Endicott (University of Oxford) , Bernard T. Golding (Newcastle University) , Karen Haggerty (Newcastle University) , Ian R. Hardcastle (Newcastle University) , Philip J. Jewsbury (AstraZeneca Pharmaceuticals) , David R. Newell (Newcastle University) , Martin E. M. Noble (University of Oxford) , Celine Roche (Newcastle University) , Lan Z. Wang (Newcastle University) , Roger J. Griffin (Newcastle University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 57 (1) , PAGES 56 - 70

State: Published (Approved)
Published: December 2013

Abstract: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a “reverse” binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these “reverse” binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

Journal Keywords: Crystallography; X-Ray; Cyclin-Dependent; Drug; Models; Molecular; Protein; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials

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

Other Facilities: ESRF