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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. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2007-07-102061v1 110/12/4055    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rix, U. Articles by Superti-Furga, G. Search for Related Content PubMed PubMed Citation Articles by Rix, U. Articles by Superti-Furga, G. Related Collections Neoplasia Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Brehme, O. Hantschel, J. Colinge, I. Kaupe, M. Planyavsky, T. Kocher, K. Mechtler, K. L. Bennett, and G. Superti-Furga Charting the molecular network of the drug target Bcr-Abl PNAS, May 5, 2009; 106(18): 7414 - 7419. [Abstract] [Full Text] [PDF] G. Yogalingam and A. M. Pendergast Abl Kinases Regulate Autophagy by Promoting the Trafficking and Function of Lysosomal Components J. Biol. Chem., December 19, 2008; 283(51): 35941 - 35953. [Abstract] [Full Text] [PDF] D. Y. H. Hallaert, A. Jaspers, C. J. van Noesel, M. H. J. van Oers, A. P. Kater, and E. Eldering c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches Blood, December 15, 2008; 112(13): 5141 - 5149. [Abstract] [Full Text] [PDF] R. Vitali, C. Mancini, V. Cesi, B. Tanno, M. Mancuso, G. Bossi, Y. Zhang, R. V. Martinez, B. Calabretta, C. Dominici, et al. Slug (SNAI2) Down-Regulation by RNA Interference Facilitates Apoptosis and Inhibits Invasive Growth in Neuroblastoma Preclinical Models Clin. Cancer Res., July 15, 2008; 14(14): 4622 - 4630. [Abstract] [Full Text] [PDF] J. S. Duncan, L. Gyenis, J. Lenehan, M. Bretner, L. M. Graves, T. A. Haystead, and D. W. Litchfield An Unbiased Evaluation of CK2 Inhibitors by Chemoproteomics: Characterization of Inhibitor Effects on CK2 and Identification of Novel Inhibitor Targets Mol. Cell. Proteomics, June 1, 2008; 7(6): 1077 - 1088. [Abstract] [Full Text] [PDF] T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF] M. Kneidinger, U. Schmidt, U. Rix, K. V. Gleixner, A. Vales, C. Baumgartner, C. Lupinek, M. Weghofer, K. L. Bennett, H. Herrmann, et al. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils Blood, March 15, 2008; 111(6): 3097 - 3107. [Abstract] [Full Text] [PDF]

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