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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Schmidt, Uwe Bürckstümmer, Tilmann Colinge, Jacques Bennett, Keiryn L. Ellmeier, Wilfried Valent, Peter Hantschel, Oliver Schütze, Gregor Superti-furga, Giulio Rix, Uwe Kneidinger, Michael |
| Description | Author Affiliation: Hantschel O ( Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 19, 1090 Vienna, Austria.); |
| Abstract | Dasatinib is a small-molecule kinase inhibitor used for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). We have analyzed the kinases targeted by dasatinib by using an unbiased chemical proteomics approach to detect binding proteins directly from lysates of CML cells. Besides Abl and Src kinases, we have identified the Tec kinases Btk and Tec, but not Itk, as major binders of dasatinib. The kinase activity of Btk and Tec, but not of Itk, was inhibited by nanomolar concentrations of dasatinib in vitro and in cultured cells. We identified the gatekeeper residue as the critical determinant of dasatinib susceptibility. Mutation of Thr-474 in Btk to Ile and Thr-442 in Tec to Ile conferred resistance to dasatinib, whereas mutation of the corresponding residue in Itk (Phe-435) to Thr sensitized the otherwise insensitive Itk to dasatinib. The configuration of this residue may be a predictor for dasatinib sensitivity across the kinome. Analysis of mast cells derived from Btk-deficient mice suggested that inhibition of Btk by dasatinib may be responsible for the observed reduction in histamine release upon dasatinib treatment. Furthermore, dasatinib inhibited histamine release in primary human basophils and secretion of proinflammatory cytokines in immune cells. The observed inhibition of Tec kinases by dasatinib predicts immunosuppressive (side) effects of this drug and may offer therapeutic opportunities for inflammatory and immunological disorders. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 33 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Protein Kinase Inhibitors Pharmacology Protein-Tyrosine Kinases Antagonists & Inhibitors Pyrimidines Thiazoles Animals Basophils Drug Effects Metabolism Dasatinib Enzyme-Linked Immunosorbent Assay Fusion Proteins, Bcr-abl Histamine Release K562 Cells Mice Mice, Inbred C57BL U937 Cells Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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