Golvatinib (E7050)

E-7050 is a potent dual inhibitor of both c-Met and VEGFR2 kinases with IC50s of 14 and 16 nM, respectively.

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> c-Met/HGFR

Research Areas >> Cancer

VEGFR2:16 nM (IC50)

c-Met:14 nM (IC50)

E7050 potently inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. E7050 strongly inhibits the growth of MKN45, EBC-1, Hs746T, and SNU-5 tumor cells with IC50 values of 37, 6.2, 23, and 24 nM, respectively. The growth of A549, SNU-1 and 0MKN74 tumor cells is inhibited by E7050 with much higher IC50 values[1]. E7050 circumvents resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevents the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF[2].

E7050 shows inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors, and strong inhibition of tumor growth and tumor angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of E7050v (50–200 mg/kg) induced tumor regression and disappearance. In a peritoneal dissemination model, E7050 shows an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice[1]. E7050 plus gefitinib results in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells[2].

Cells (1000-3000 cells/100 μL/well) are seeded on 96-well culture plates with various concentrations of E7050 and cultured for 3 days. Then, 10 μL of WST-8 reagent is added to each well, and absorbance is measured at 450 nm compared with a reference measurement at 660 nm using a MTP-500 microplate reader[1].

Mice: Nude mice bearing MKN45, Hs746T, SNU-5, or EBC-1 tumors are administered E7050 (25, 50, 100, 200 mg/kg) or vehicle only as a control, once a day. Tumor volume is measured using calipers on the indicated days (0-15 days)[1].

[1]. Nakagawa T et al. E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models. Cancer Sci, 2010, 101(1), 210-215.

[2]. Wang W et al. Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer. Clin Cancer Res, 2012, 18(6), 1663-1671.

Nintedanib (BIBF 1120) | SU5416 | Apatinib Mesylate | PD173074 | Capmatinib (INCB28060) | Foretinib (GSK1363089) | PHA-665752 | SU 5402 | Linifanib (ABT-869) | Cediranib | Lucitanib | RAF265 (CHIR-265) | LY2784544 | BMS-777607 | SU14813