Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets
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- Uwe Rix
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Oliver Hantschel
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Gerhard Dürnberger
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Lily L. Remsing Rix
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Melanie Planyavsky
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Nora V. Fernbach
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Ines Kaupe
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Keiryn L. Bennett
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
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- Jacques Colinge
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Thomas Köcher
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
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- Giulio Superti-Furga
- Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and
説明
<jats:title>Abstract</jats:title> <jats:p>The BCR-ABL tyrosine kinase inhibitor imatinib represents the current frontline therapy in chronic myeloid leukemia. Because many patients develop imatinib resistance, 2 second-generation drugs, nilotinib and dasatinib, displaying increased potency against BCR-ABL were developed. To predict potential side effects and novel medical uses, we generated comprehensive drug-protein interaction profiles by chemical proteomics for all 3 drugs. Our studies yielded 4 major findings: (1) The interaction profiles of the 3 drugs displayed strong differences and only a small overlap covering the ABL kinases. (2) Dasatinib bound in excess of 30 Tyr and Ser/Thr kinases, including major regulators of the immune system, suggesting that dasatinib might have a particular impact on immune function. (3) Despite the high specificity of nilotinib, the receptor tyrosine kinase DDR1 was identified and validated as an additional major target. (4) The oxidoreductase NQO2 was bound and inhibited by imatinib and nilotinib at physiologically relevant drug concentrations, representing the first nonkinase target of these drugs.</jats:p>
収録刊行物
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- Blood
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Blood 110 (12), 4055-4063, 2007-12-01
American Society of Hematology