YM-231146, a Novel Orally Bioavailable Inhibitor of Vascular Endothelial Growth Factor Receptor-2, Is Effective against Paclitaxel Resistant Tumors

• Published in: Biological & Pharmaceutical Bulletin Vol. 28; no. 11; pp. 2096 - 2101
• Main Authors: Amino, Nobuaki, Ideyama, Yukitaka, Yamano, Mayumi, Kuromitsu, Sadao, Tajinda, Katsunori, Samizu, Kiyohiro, Matsuhisa, Akira, Shirasuna, Kenna, Kudoh, Masafumi, Shibasaki, Masayuki
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.11.2005; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: angiogenesis; Angiogenesis Inhibitors - pharmacokinetics; Angiogenesis Inhibitors - pharmacology; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Biological Availability; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm; endothelial cell; Humans; Mice; Mice, Nude; Morpholines - pharmacokinetics; Morpholines - pharmacology; multidrug resistance (MDR); Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - pathology; Neovascularization, Pathologic - prevention & control; paclitaxel; Paclitaxel - pharmacology; Phosphorylation; Quinolines - pharmacokinetics; Quinolines - pharmacology; vascular endothelial growth factor (VEGF); Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; YM-231146
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.28.2096

Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition. The result was YM-231146 (IC50=0.080 μM). YM-231146 inhibited VEGF-stimulated proliferation, VEGF-R2 autophosphorylation, and vessel sprout formation of human vascular endothelial cells at concentrations between 0.15—0.30 μM. However, YM-231146 did not inhibit cancer cell proliferation at these concentrations (IC50>5 μM). In the in vivo studies, once-daily oral dosing of YM-231146 to human cancer xenografts elicited antitumor activity at doses of 3—100 mg/kg. Moreover, YM-231146 completely inhibited tumor growth of paclitaxel-resistant cancer cells without decreasing body weight at a dose of 100 mg/kg. These results suggest that YM-231146 is a novel orally bioavailable inhibitor of VEGF-R2 that would be useful for the treatment of multidrug resistant tumors.