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

Nobuaki Amino; Yukitaka Ideyama; Mayumi Yamano; Sadao Kuromitsu; Katsunori Tajinda; Kiyohiro Samizu; Akira Matsuhisa; Kenna Shirasuna; Masafumi Kudoh; Masayuki Shibasaki

doi:10.1248/bpb.28.2096

Regular Articles

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

Nobuaki Amino, Yukitaka Ideyama, Mayumi Yamano, Sadao Kuromitsu, Katsunori Tajinda, Kiyohiro Samizu, Akira Matsuhisa, Kenna Shirasuna, Masafumi Kudoh, Masayuki Shibasaki

Author information

Nobuaki Amino
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Yukitaka Ideyama
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Mayumi Yamano
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Sadao Kuromitsu
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Katsunori Tajinda
Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Kiyohiro Samizu
Chemistry Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Akira Matsuhisa
Lead Discovery Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Kenna Shirasuna
Discovery Metabolism Research, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Masafumi Kudoh
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
Masayuki Shibasaki
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.

Keywords: YM-231146, angiogenesis, endothelial cell, vascular endothelial growth factor (VEGF), multidrug resistance (MDR), paclitaxel

JOURNAL FREE ACCESS

2005 Volume 28 Issue 11 Pages 2096-2101

DOI https://doi.org/10.1248/bpb.28.2096

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Abstract

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.

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