The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has Marked<i>In Vivo</i>Antitumor Properties and a Favorable Tolerability Profile

Hidenori Fujita, Kazutaka Miyadera, Masanori Kato, Yayoi Fujioka, Hiroaki Ochiiwa, Jinhong Huang, Kimihiro Ito, Yoshimi Aoyagi, Toru Takenaka, Takamasa Suzuki, Satoko Ito, Akihiro Hashimoto, Takashi Suefuji, Kosuke Egami, Hideki Kazuno, Yoshimitsu Suda, Kazuto Nishio, Kazuhiko Yonekura

doi:10.1158/1535-7163.mct-13-0459

<jats:title>Abstract</jats:title><jats:p>VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 μmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer–bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685–96. ©2013 AACR.</jats:p>

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has Marked<i>In Vivo</i>Antitumor Properties and a Favorable Tolerability Profile

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The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has Marked<i>In Vivo</i>Antitumor Properties and a Favorable Tolerability Profile

説明

収録刊行物

被引用文献 (6)*注記

参考文献 (50)*注記

関連プロジェクト

キーワード

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書き出し

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