Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives

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

doi:10.1021/jm020056z

Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives

J Med Chem. 2002 Aug 1;45(16):3381-93. doi: 10.1021/jm020056z.

Authors

Ashleigh E Gibson¹, 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

Affiliation

¹ Department of Chemistry and Cancer Research Unit, University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom.

PMID: 12139449
DOI: 10.1021/jm020056z

Abstract

O(6)-substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O(6) substituent occupying the kinase ribose binding site. Fifty-eight O(6)-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 O(6) 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 O(6)-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Binding Sites
CDC2 Protein Kinase / antagonists & inhibitors
CDC2 Protein Kinase / metabolism*
CDC2-CDC28 Kinases*
Cell Division / drug effects
Crystallography, X-Ray
Cyclin A / metabolism
Cyclin B / metabolism
Cyclin B1
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases / antagonists & inhibitors
Cyclin-Dependent Kinases / metabolism*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Guanine / analogs & derivatives*
Guanine / chemical synthesis*
Guanine / chemistry
Guanine / pharmacology
Humans
Models, Molecular
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism*
Ribose / metabolism*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
CCNB1 protein, human
Cyclin A
Cyclin B
Cyclin B1
Enzyme Inhibitors
Guanine
Ribose
Adenosine Triphosphate
Protein Serine-Threonine Kinases
CDC2 Protein Kinase
CDC2-CDC28 Kinases
CDK2 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases