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

Science. 1998 Jul 24;281(5376):533-8. doi: 10.1126/science.281.5376.533.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / metabolism
  • Adenine / pharmacology
  • Binding Sites
  • CDC2-CDC28 Kinases*
  • CDC28 Protein Kinase, S cerevisiae / antagonists & inhibitors
  • Cell Division / drug effects
  • Crystallography, X-Ray
  • Cyclin A / metabolism
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Drug Evaluation, Preclinical
  • Flavonoids / chemistry
  • Flavonoids / metabolism
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Fungal / drug effects
  • Genes, Fungal
  • Humans
  • Hydrogen Bonding
  • Oligonucleotide Probes
  • Phosphates / metabolism
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Purines / chemical synthesis
  • Purines / chemistry
  • Purines / metabolism
  • Purines / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects
  • Tumor Cells, Cultured

Substances

  • Cyclin A
  • Flavonoids
  • Oligonucleotide Probes
  • Phosphates
  • Piperidines
  • Purines
  • RNA, Messenger
  • purvalanol B
  • alvocidib
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDC28 Protein Kinase, S cerevisiae
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Adenine

Associated data

  • PDB/1CKP