jm020056z_si_001.pdf (46.73 kB)
Download fileProbing the ATP Ribose-Binding Domain of Cyclin-Dependent Kinases 1 and 2 with O6-Substituted Guanine Derivatives
journal contribution
posted on 2002-07-04, 00:00 authored 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. WhitfieldO6-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.