title: Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling.
abstract: 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.
authors.affiliation: Axxima Pharmaceuticals AG, Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Godl
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Gruss
authors.forename: Jan
authors.initials: J
authors.lastname: Eickhoff
authors.forename: Josef
authors.initials: J
authors.lastname: Wissing
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blencke
authors.forename: Martina
authors.initials: M
authors.lastname: Weber
authors.forename: Heidrun
authors.initials: H
authors.lastname: Degen
authors.forename: Dirk
authors.initials: D
authors.lastname: Brehmer
authors.forename: László
authors.initials: L
authors.lastname: Orfi
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Horváth
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Matt
authors.initials: M
authors.lastname: Cotten
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.forename: Henrik
authors.initials: H
authors.lastname: Daub
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D064127:Aurora Kinases; D019556:COS Cells; D002455:Cell Division / Q000187:drug effects; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D000078183:Oxindoles; D011422:Propionates; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D014162:Transfection
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C412603:orantinib; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human