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 Blood, 1 December 2007, Vol. 110, No. 12, pp. 4055-4063.
Prepublished online as a Blood First Edition Paper on August 24, 2007; DOI 10.1182/blood-2007-07-102061.

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NEOPLASIA

Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets

Uwe Rix1, Oliver Hantschel1, Gerhard Dürnberger1, Lily L. Remsing Rix1, Melanie Planyavsky1, Nora V. Fernbach1, Ines Kaupe1, Keiryn L. Bennett1, Peter Valent2, Jacques Colinge1, Thomas Köcher1, and Giulio Superti-Furga1

1 Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna; and 2 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

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.


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