Characterization of a Conserved Structural Determinant Controlling Protein Kinase Sensitivity to Selective Inhibitors

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Chemistry & biology 2004-05, Vol.11 (5), p.691-701
Hauptverfasser: Blencke, Stephanie, Zech, Birgit, Engkvist, Ola, Greff, Zoltán, Őrfi, László, Horváth, Zoltán, Kéri, György, Ullrich, Axel, Daub, Henrik
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:1074-5521
1879-1301
DOI:10.1016/j.chembiol.2004.02.029