title: The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile.
abstract: 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.
authors.affiliation: Corresponding Author: Hidenori Fujita, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. hide-fujita@taiho.co.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Fujita
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Miyadera
authors.forename: Masanori
authors.initials: M
authors.lastname: Kato
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Fujioka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ochiiwa
authors.forename: Jinhong
authors.initials: J
authors.lastname: Huang
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Ito
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Aoyagi
authors.forename: Toru
authors.initials: T
authors.lastname: Takenaka
authors.forename: Takamasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Satoko
authors.initials: S
authors.lastname: Ito
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hashimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Suefuji
authors.forename: Kosuke
authors.initials: K
authors.lastname: Egami
authors.forename: Hideki
authors.initials: H
authors.lastname: Kazuno
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Suda
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yonekura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D013890:Thiourea; C000590217:4-(2-fluoro-4-((((2-phenylacetyl)amino)thioxomethyl)amino)phenoxy)-7-methoxy-N-methyl-6-quinolinecarboxamide