Document Detail


Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.
MedLine Citation:
PMID:  12139449     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  45     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-07-25     Completed Date:  2002-08-19     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3381-93     Citation Subset:  IM    
Affiliation:
Department of Chemistry and Cancer Research Unit, University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism*
Antineoplastic Agents / chemical synthesis,  chemistry,  pharmacology
Binding Sites
CDC2 Protein Kinase / antagonists & inhibitors,  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,  metabolism*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis*,  chemistry,  pharmacology
Guanine / analogs & derivatives*,  chemical synthesis*,  chemistry,  pharmacology
Humans
Models, Molecular
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  metabolism*
Ribose / metabolism*
Structure-Activity Relationship
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CCNB1 protein, human; 0/Cyclin A; 0/Cyclin B; 0/Cyclin B1; 0/Enzyme Inhibitors; 50-69-1/Ribose; 56-65-5/Adenosine Triphosphate; 73-40-5/Guanine; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.22/CDC2 Protein Kinase; EC 2.7.11.22/CDC2-CDC28 Kinases; EC 2.7.11.22/CDK2 protein, human; EC 2.7.11.22/Cyclin-Dependent Kinase 2; EC 2.7.11.22/Cyclin-Dependent Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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