title: E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models.
abstract: c-Met is the cellular receptor for hepatocyte growth factor (HGF) and is known to be dysregulated in various types of human cancers. Activation of the HGF/c-Met pathway causes tumor progression, invasion, and metastasis. Vascular endothelial growth factor (VEGF) is also known as a key molecule in tumor progression through the induction of tumor angiogenesis. Because of their key roles in tumor progression, these pathways provide attractive targets for therapeutic intervention. We have generated a novel, orally active, small molecule compound, E7050, which inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2. In vitro studies indicate that E7050 potently inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In vivo studies using E7050 showed inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors, and strong inhibition of tumor growth and tumor angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of E7050 (50-200 mg/kg) induced tumor regression and disappearance. In a peritoneal dissemination model, E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. Our results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer.
authors.affiliation: Tsukuba Research Laboratory, Eisai Co, Ltd, Ibaraki, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Tohyama
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
authors.forename: Keiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Setsuo
authors.initials: S
authors.lastname: Funasaka
authors.forename: Shuji
authors.initials: S
authors.lastname: Shirotori
authors.forename: Makoto
authors.initials: M
authors.lastname: Asada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Obaishi
mesh_terms: D000631:Aminopyridines / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; C548173:N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)carbonylaminopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2