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...

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Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 65; no. 15; pp. 6919 - 6926
Main Authors GODL, Klaus, GRUSS, Oliver J, KERI, György, MÜLLER, Stefan, COTTON, Matt, ULLRICH, Axel, DAUB, Henrik, EICKHOFF, Jan, WISSING, Josef, BLENCKE, Stephanie, WEBER, Martina, DEGEN, Heidrun, BREHMER, Dirk, ÖRFI, Laszlo, HORVATH, Zoltan
Format Journal Article
LanguageEnglish
Published Philadelphia, PA American Association for Cancer Research 01.08.2005
Subjects
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Aurora Kinases
Biological and medical sciences
Cell Division - drug effects
Cercopithecus aethiops
COS Cells
HeLa Cells
Humans
Indoles - pharmacology
Medical sciences
Pharmacology. Drug treatments
Protein Kinase Inhibitors - pharmacology
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Pyrroles - pharmacology
Transfection
Tumors
Characterization
Signaling pathway
Antiangiogenic agent
In vitro
Proteomics
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Summary: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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ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-05-0574