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

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 7; pp. 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: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.04.2006; Elsevier
• 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; KDR; PDGFR; Inhibitor; Biological results; FGFR; Pyrimidopyrimidone; Antineoplastic agent; Fibroblast growth factor; Angiogenic factor; Vascularization; Angiogenesis; Signal transduction; Inhibition; Small molecule; Neovascularization; Antiangiogenic agent; Protein-tyrosine kinase; Platelet derived growth factor; Enzyme; Transferases; Rodentia; Oral administration; In vitro; Biological activity; In vivo; Vertebrata; Growth factor receptor; Pyrimidopyrimidone: KDR; Mammalia; Vascular endothelium growth factor; Synthetic product; Animal; Models; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.12.092

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.