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8-Substituted O-6-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode

Lookup NU author(s): Dr Benoit Carbain, Dr Allyson Campbell, Dr Celine Cano, Professor Jane Endicott, Professor Bernard Golding, Dr Karen Haggerty, Dr Ian Hardcastle, Professor Herbie Newell, Professor Martin Noble, Dr Celine Roche, Lan Wang, Professor Roger Griffin

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O-6-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 degrees. 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.


Publication metadata

Author(s): Carbain B, Paterson DJ, Anscombe E, Campbell AJ, Cano C, Echalier A, Endicott JA, Golding BT, Haggerty K, Hardcastle IR, Jewsbury PJ, Newell DR, Noble MEM, Roche C, Wang LZ, Griffin RJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2014

Volume: 57

Issue: 1

Pages: 56-70

Print publication date: 04/12/2013

Online publication date: 04/12/2013

Acceptance date: 01/01/1900

Date deposited: 18/02/2016

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/jm401555v

DOI: 10.1021/jm401555v


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