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  • Title: Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors.
    Author: Blencke S, Zech B, Engkvist O, Greff Z, Orfi L, Horváth Z, Kéri G, Ullrich A, Daub H.
    Journal: Chem Biol; 2004 May; 11(5):691-701. PubMed ID: 15157880.
    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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