Biol. Pharm. Bull., 28(11),2096-2101, November 2005

Regular Articles

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

Nobuaki AMINO,^a Yukitaka IDEYAMA,^a Mayumi YAMANO,^a Sadao KUROMITSU,^b Katsunori TAJINDA,^b Kiyohiro SAMIZU,^c Akira MATSUHISA,^d Kenna SHIRASUNA,^e Masafumi KUDOH,^a and Masayuki SHIBASAKI^a

^a Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; ^b Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; ^c Chemistry Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; ^d Lead Discovery Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; and ^e Discovery Metabolism Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.; 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. * To whom correspondence should be addressed. e-mail: nobuaki.amino@jp.astellas.com

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.

Key words YM-231146; angiogenesis; endothelial cell; vascular endothelial growth factor (VEGF); multidrug resistance (MDR); paclitaxel