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Molecular Targets for Therapy

A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells

Leukemia volume 24, pages 44–50 (2010)Cite this article

Abstract

Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.

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Acknowledgements

This study was supported by the Leukemia and Lymphoma Society (Grant number 5081–05), the Austrian Federal Ministry for Science and Research (BMWF) under the GEN-AU program (GZ200.142/I-VI/I/2006 and GZ200.145/I-VI/I/2006), the Austrian Science Fund (FWF; P18737-B11), the Austrian National Bank (ÖNB) and the Austrian Academy of Sciences (ÖAW). We thank Norbert Venturini for preparation of the SDS–PAGE gels and Florian Grebien for helpful discussions.

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Author notes

  1. U Rix and L L Remsing Rix: These authors contributed equally to this work.

Authors and Affiliations

  1. CeMM - Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    U Rix, L L Remsing Rix, N V Fernbach, O Hantschel, M Planyavsky, F P Breitwieser, J Colinge, K L Bennett & G Superti-Furga

  2. Division of Hematology and Medical Oncology, Portland VA Medical Center and OHSU Knight Cancer Institute, Portland, OR, USA

    A S Terker & M C Heinrich

  3. Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria

    H Herrmann & P Valent

  4. Millipore UK Ltd, Dundee, UK

    M Augustin & J H Till

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  1. U Rix
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Correspondence to G Superti-Furga.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Rix, U., Remsing Rix, L., Terker, A. et al. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia 24, 44–50 (2010). https://doi.org/10.1038/leu.2009.228

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