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Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors

Clifford D Mol1, Doriano Fabbro, David J Hosfield

  • 1Syrrx Inc, La Jolla, CA 92121, USA. clifford.mol@syrrx.com

Current Opinion in Drug Discovery & Development
|October 27, 2004
PubMed

Insights

Gleevec (STI-571) is a successful cancer drug targeting Abelson kinase. Structural studies reveal similar inactive kinase features, aiding future targeted cancer drug discovery.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • STI-571 (Gleevec) is a targeted cancer therapy.
  • It inhibits Abelson cytoplasmic tyrosine kinase (Abl), crucial in chronic myelogenous leukemia.
  • STI-571 also targets c-Kit and platelet-derived growth factor receptor kinases.

Purpose of the Study:

  • To review recent X-ray co-crystal structure analyses of STI-571.
  • To examine structures of STI-571 bound to Abl and c-Kit.
  • To analyze three additional kinase inhibitor co-crystal structures.

Main Methods:

  • X-ray crystallography
  • Co-crystal structure analysis
  • Kinase inhibitor structural studies

Main Results:

  • Detailed structural insights into STI-571 binding to Abl and c-Kit.
  • Identification of similar structural features in inactive conformations of targeted kinases.
  • Analysis of three other relevant kinase inhibitor co-crystal structures.

Conclusions:

  • The conserved structural features of inactive kinases provide a template for drug design.
  • This knowledge facilitates the development of novel, specific, gene-based cancer drugs.
  • Structural biology advances are key to targeted cancer therapy innovation.

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