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Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O6-substituted guanine derivatives

Lookup NU author(s): Dr Ashleigh Gibson, Dr Christine Arris, Dr Johanne Bentley, Professor Nicola Curtin, Professor Jane Endicott, Professor Bernard Golding, Professor Roger Griffin, Dr Veronique Mesguiche, Professor Herbie Newell, Professor Martin Noble, Hayley Whitfield

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Abstract

O6-Substituted guanines are adenosine 5′-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O6 substituent occupying the kinase ribose binding site. Fifty-eight O6-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic O6 substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O6-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.


Publication metadata

Author(s): Gibson A, Arris CE, Bentley J, Boyle F, Curtin NJ, Davies T, Endicott J, Golding BT, Grant S, Griffin R, Jewsbury, P., Johnson, L., Mesguiche, V., Newell, D.R., Noble, M., Tucker, J., Whitfield, H.J.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2002

Volume: 45

Issue: 16

Pages: 3381-3393

Print publication date: 01/08/2002

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm020056z

DOI: 10.1021/jm020056z

PubMed id: 12139449


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