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Molecular Targets for Therapy

Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Leukemia volume 23, pages 477–485 (2009)Cite this article

Abstract

The detailed molecular mechanism of action of second-generation BCR–ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

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Acknowledgements

This work 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 Melanie Planyavsky for preparation of the SDS-PAGE gels, Gerhard Dürnberger for assistance in bioinformatics analyses and the Superti-Furga group for helpful discussions.

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Authors and Affiliations

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

    L L Remsing Rix, U Rix, J Colinge, O Hantschel, K L Bennett, T Stranzl, A Müller & G Superti-Furga

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

    C Baumgartner & P Valent

  3. Millipore UK Ltd, Gemini Crescent, Dundee Technology Park, Dundee, UK

    M Augustin & J H Till

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  1. L L Remsing 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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Remsing Rix, L., Rix, U., Colinge, J. et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 23, 477–485 (2009). https://doi.org/10.1038/leu.2008.334

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