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Lookup NU author(s): Dr Benoit Carbain, Dr Allyson Campbell, Dr Celine CanoORCiD, Professor Jane Endicott, Emeritus Professor Bernard Golding, Dr Karen Haggerty, Dr Ian HardcastleORCiD, Professor Herbie Newell, Professor Martin NobleORCiD, Dr Celine Roche, Lan Wang, Professor Roger Griffin
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
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.
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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