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Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling

Klaus Godl¹, Oliver J. Gruss², Jan Eickhoff¹, Josef Wissing^1,3, Stephanie Blencke¹, Martina Weber¹, Heidrun Degen¹, Dirk Brehmer¹, László rfi⁴, Zoltán Horváth⁴, György Kéri⁴, Stefan Müller¹, Matt Cotten¹, Axel Ullrich^5,6 and Henrik Daub¹

¹ Axxima Pharmaceuticals AG, Munich, Germany; ² ZMBH, Heidelberg, Germany; ³ Department of Cell Biology, GBF, Braunschweig, Germany; ⁴ Vichem Chemie Ltd., Budapest, Hungary; ⁵ Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany; and ⁶ Centre for Molecular Medicine, Agency for Science, Technology, and Research, Proteos, Singapore

Requests for reprints: Henrik Daub, Department of Molecular Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18A, Martinsried 82152, Germany. Phone: 49-89-8578-3773; E-mail: daub{at}biochem.mpg.de.

Knowledge about molecular drug action is critical for the development of protein kinase inhibitors for cancer therapy. Here, we establish a chemical proteomic approach to profile the anticancer drug SU6668, which was originally designed as a selective inhibitor of receptor tyrosine kinases involved in tumor vascularization. By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1. Importantly, a cell cycle block induced by SU6668 could be attributed to inhibition of Aurora kinase activity. Moreover, SU6668 potently suppressed antiviral and inflammatory responses by interfering with TANK-binding kinase 1–mediated signal transmission. These results show the potential of chemical proteomics to provide rationales for the development of potent kinase inhibitors, which combine rather unexpected biological modes of action by simultaneously targeting defined sets of both serine/threonine and tyrosine kinases involved in cancer progression.

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