Reference Detail

Ref Type

Journal Article

PMID

(24140932)

Authors

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	12	12	2013 Dec	2685-96	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TAS-115	TAS-115	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TAS-115			MET Inhibitor 59 VEGFR2 Inhibitor 37	TAS-115 is a small molecule inhibitor of MET and KDR (VEGFR2), which may lead to angiogenesis blockade and tumor regression (PMID: 24140932, PMID: 31820255).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References