Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis

The biological evaluation of RO4396686, an inhibitor of the key pro-angiogenic kinases KDR, FGFR, and PDGFR is reported. RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited...

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Published in:Bioorganic & medicinal chemistry letters 2006-04, Vol.16 (7), p.1950-1953
Main Authors: McDermott, Lee A., Higgins, Brian, Simcox, Mary, Luk, Kin-Chun, Nevins, Tom, Kolinsky, Kenneth, Smith, Melissa, Yang, Hong, Li, Jia K., Chen, Yingsi, Ke, June, Mallalieu, Navita, Egan, Tom, Kolis, Stan, Railkar, Aruna, Gerber, Louise, Liu, Jin-Jun, Konzelmann, Fred, Zhang, Zhuming, Flynn, Tom, Morales, Omar, Chen, Yi
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Biological and medical sciences
Biological results
FGFR
General aspects
Inhibitor
KDR
Medical sciences
Mice
Mice, Nude
Neoplasms, Experimental - blood supply
Neovascularization, Pathologic
PDGFR
Pharmacology. Drug treatments
Pyrimidines - pharmacology
Pyrimidopyrimidone
Rats
Rats, Wistar
Receptors, Fibroblast Growth Factor - antagonists & inhibitors
Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors
Vascular Endothelial Growth Factor A - physiology
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
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Summary:The biological evaluation of RO4396686, an inhibitor of the key pro-angiogenic kinases KDR, FGFR, and PDGFR is reported. RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited VEGF-induced angiogenesis. Tested in a H460a xenograft tumor model this agent effected significant tumor growth inhibition at doses as low as 50 mg/kg.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.12.092