Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors - PubMed (original) (raw)

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

Stephanie Blencke et al. Chem Biol. 2004 May.

Free article

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 betaPDGF 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.

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A hot spot for protein kinase inhibitor sensitivity.
Bishop AC. Bishop AC. Chem Biol. 2004 May;11(5):587-9. doi: 10.1016/j.chembiol.2004.05.002. Chem Biol. 2004. PMID: 15157868

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Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors - PubMed (original) (raw)