RRC ID 69450
Author Fujita H, Miyadera K, Kato M, Fujioka Y, Ochiiwa H, Huang J, Ito K, Aoyagi Y, Takenaka T, Suzuki T, Ito S, Hashimoto A, Suefuji T, Egami K, Kazuno H, Suda Y, Nishio K, Yonekura K.
Title The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile.
Journal Mol Cancer Ther
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.
Volume 12(12)
Pages 2685-96
Published 2013-12-1
DOI 10.1158/1535-7163.MCT-13-0459
PII 1535-7163.MCT-13-0459
PMID 24140932
MeSH Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Antineoplastic Agents / toxicity Cell Line, Tumor Cell Proliferation / drug effects Disease Models, Animal Endothelial Cells / drug effects Endothelial Cells / metabolism Enzyme Activation / drug effects Humans Mice Neovascularization, Pathologic / drug therapy Neovascularization, Pathologic / metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / administration & dosage Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / toxicity Proto-Oncogene Proteins c-met / antagonists & inhibitors* Quinolines / administration & dosage Quinolines / pharmacology* Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors* Thiourea / administration & dosage Thiourea / analogs & derivatives* Thiourea / pharmacology Tumor Burden / drug effects Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors Xenograft Model Antitumor Assays
IF 5.615
Human and Animal Cells NUGC-4(RCB1939)