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,
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
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
Print publication date: 01/08/2002
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
PubMed id: 12139449
Altmetrics provided by Altmetric