Publication Date:
1998-07-24
Description:
Selective protein kinase inhibitors were developed on the basis of the unexpected binding mode of 2,6,9-trisubstituted purines to the adenosine triphosphate-binding site of the human cyclin-dependent kinase 2 (CDK2). By iterating chemical library synthesis and biological screening, potent inhibitors of the human CDK2-cyclin A kinase complex and of Saccharomyces cerevisiae Cdc28p were identified. The structural basis for the binding affinity and selectivity was determined by analysis of a three-dimensional crystal structure of a CDK2-inhibitor complex. The cellular effects of these compounds were characterized in mammalian cells and yeast. In the latter case the effects were characterized on a genome-wide scale by monitoring changes in messenger RNA levels in treated cells with high-density oligonucleotide probe arrays. Purine libraries could provide useful tools for analyzing a variety of signaling and regulatory pathways and may lead to the development of new therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gray, N S -- Wodicka, L -- Thunnissen, A M -- Norman, T C -- Kwon, S -- Espinoza, F H -- Morgan, D O -- Barnes, G -- LeClerc, S -- Meijer, L -- Kim, S H -- Lockhart, D J -- Schultz, P G -- New York, N.Y. -- Science. 1998 Jul 24;281(5376):533-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9677190" target="_blank"〉PubMed〈/a〉
Keywords:
Adenine/*analogs & derivatives/chemistry/metabolism/pharmacology
;
Binding Sites
;
*CDC2-CDC28 Kinases
;
CDC28 Protein Kinase, S cerevisiae/antagonists & inhibitors
;
Cell Division/drug effects
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Crystallography, X-Ray
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Cyclin A/metabolism
;
Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases/*antagonists & inhibitors
;
Drug Evaluation, Preclinical
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Flavonoids/chemistry/metabolism/pharmacology
;
Gene Expression Regulation, Fungal/drug effects
;
Genes, Fungal
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Humans
;
Hydrogen Bonding
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Oligonucleotide Probes
;
Phosphates/metabolism
;
Piperidines/chemistry/metabolism/pharmacology
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors
;
Purines/chemical synthesis/chemistry/metabolism/*pharmacology
;
RNA, Messenger/genetics/metabolism
;
Saccharomyces cerevisiae/enzymology/genetics
;
Structure-Activity Relationship
;
Transcription, Genetic/drug effects
;
Tumor Cells, Cultured
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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