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Probing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with O6-Substituted Guanine Derivatives

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posted on 04.07.2002, 00:00 by Ashleigh E. Gibson, Christine E. Arris, Johanne Bentley, F. Thomas Boyle, Nicola J. Curtin, Thomas G. Davies, Jane A. Endicott, Bernard T. Golding, Sharon Grant, Roger J. Griffin, Philip Jewsbury, Louise N. Johnson, Veronique Mesguiche, David R. Newell, Martin E. M. Noble, Julie A. Tucker, Hayley J. Whitfield
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.

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