Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors

Stephanie Blencke, Birgit Zech, Ola Engkvist, Zoltán Greff, László Orfi, Zoltán Horváth, György Kéri, Axel Ullrich, Henrik Daub

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Some protein kinases are known to acquire resistance to selective small molecule inhibitors upon mutation of a conserved threonine at the ATP binding site to a larger residue. Here, we performed a comprehensive mutational analysis of this structural element and determined the cellular sensitivities of several disease-relevant tyrosine kinases against various inhibitors. Mutant kinases possessing a larger side chain at the critical site showed resistance to most compounds tested, such as ZD1839, PP1, AG1296, STI571, and a pyrido[2,3-d]pyrimidine inhibitor. In contrast, indolinones affected both wild-type and mutant kinases with similar potencies. Resistant mutants were established for pharmacological analysis of βPDGF receptor-mediated signaling and allowed the generation of a drug-inducible system of cellular Src kinase activity. Our data establish a conserved structural determinant of protein kinase sensitivity relevant for both signal transduction research and drug development.

Original languageEnglish
Pages (from-to)691-701
Number of pages11
JournalChemistry and Biology
Volume11
Issue number5
DOIs
Publication statusPublished - May 1 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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