Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling.
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.
Godl
Klaus
K
Axxima Pharmaceuticals AG, Munich, Germany.
Gruss
Oliver J
OJ
Eickhoff
Jan
J
Wissing
Josef
J
Blencke
Stephanie
S
Weber
Martina
M
Degen
Heidrun
H
Brehmer
Dirk
D
Orfi
László
L
Horváth
Zoltán
Z
Kéri
György
G
Müller
Stefan
S
Cotten
Matt
M
Ullrich
Axel
A
Daub
Henrik
H
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
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