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Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors

Academic Article
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Overview

authors

  • Gray, N. S.
  • Wodicka, L.
  • Thunnissen, Amwh
  • Norman, T. C.
  • Kwon, S. J.
  • Espinoza, F. H.
  • Morgan, D. O.
  • Barnes, G.
  • LeClerc, S.
  • Meijer, L.
  • Kim, S. H.
  • Lockhart, D. J.
  • Schultz, Peter

publication date

  • July 1998

journal

  • Science  Journal

abstract

  • 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.

subject areas

  • Adenine
  • Binding Sites
  • CDC2-CDC28 Kinases
  • CDC28 Protein Kinase, S cerevisiae
  • Cell Division
  • Crystallography, X-Ray
  • Cyclin A
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Drug Evaluation, Preclinical
  • Flavonoids
  • Gene Expression Regulation, Fungal
  • Genes, Fungal
  • Humans
  • Hydrogen Bonding
  • Oligonucleotide Probes
  • Phosphates
  • Piperidines
  • Protein-Serine-Threonine Kinases
  • Purines
  • RNA, Messenger
  • Saccharomyces cerevisiae
  • Structure-Activity Relationship
  • Transcription, Genetic
  • Tumor Cells, Cultured
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Identity

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.281.5376.533

PubMed ID

  • 9677190
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Additional Document Info

start page

  • 533

end page

  • 538

volume

  • 281

issue

  • 5376

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