Golvatinib (also known as E7050) is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family. c-Met and VEGFR-2 play important roles in tumor cell growth, migration and angiogenesis. Golvatinib (E7050) inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. In vitro, Golvatinib (E7050) circumvented 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. Golvatinib (E7050) plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells in the in vivo model. Golvatinib is currently under evaluation in a phase I clinical trial, it may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
|Cell lines||MKN45, SNU-5, Hs746, TEBC-1, MKN74, SNU-1 and A549 cells line|
|Preparation method||Cell proliferation assay.
Cells (1-3*103 cells/100 uL/well) were seeded on 96-well culture plates with various concentrations of E7050 and cultured for 3 days. Then, 10 uL of CCK-8 reagent was added to each well, and absorbance was measured at 450 nm compared with a reference measurement at 660 nm using a MTP-500 microplate reader (Corona Electric, Ibaraki, Japan). Proliferation assays using HUVEC were performed as described previously. Briefly, HUVEC (2*103 cells/well) were cultured for 3 days in medium containing HGF (30 ng/mL), VEGF (20 ng/mL) (R&D Systems), or basic fibroblast growth factor (bFGF) (20 ng/mL) (Wako Pure Chemicals, Osaka, Japan) together with serially diluted E7050.
|Incubation time||3 days|
|Animal models||Nude mice bearing MKN45 (a), Hs746T (b), SNU-5 (c), or EBC-1 (d) tumors model|
|Dosages||25, 50, 100 or 200mg/kg daily for15 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Met kinase inhibitor E7050 reverses three different mechanisms of hepatocyte growth factor-induced tyrosine kinase inhibitor resistance in EGFR mutant lung cancer.
Wang W, et al. Clin Cancer Res. 2012 Mar 15;18(6):1663-71. PMID: 22317763.
E7050: a dual c-Met and VEGFR-2 tyrosine kinase inhibitor promotes tumor regression and prolongs survival in mouse xenograft models.
Nakagawa T, et al. Cancer Sci. 2010 Jan;101(1):210-5. PMID: 19832844.
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Altiratinib(DCC-2701) is a novel c-MET/TIE-2/VEGFR inhibitor; effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro.
MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB.
NVP-BVU972 is a selective and potent Met inhibitor with IC50 of 14 nM.
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