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    Golvatinib (E7050)
    Golvatinib (E7050)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0524
    CAS #: 928037-13-2Purity ≥98%

    Description: Golvatinib (formerly E-7050) is an orally bioavailable dual c-Met and VEGFR-2 inhibitor with potential antineoplastic activity. It inhibits c-Met and VEGFR-2 with IC50 of 14 nM and 16 nM,  and shows no effects on bFGF-stimulated HUVEC growth (up to 1000 nM). Golvatinib shows potent anti-proliferative activity in vitro and high in vivo antitumor efficacy by binding to and inhibiting the activities of both c-Met and VEGFR-2, which are upregulated in various tumors and play important roles in tumor cell growth, migration and angiogenesis.

    References: Cancer Sci. 2010;101(1):210-5; Clin Cancer Res. 2012;18(6):1663-71; Am J Pathol. 2012;181(3):1034-43.

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    Molecular Weight (MW)633.69
    FormulaC33H37F2N7O4
    CAS No.928037-13-2
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 20 mg/mL (31.6 mM)
    Water: <1 mg/mL
    Ethanol:<1 mg/mL
    Solubility (In vivo)30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
    Synonyms

    Synonym: E 7050; Golvatinib; E7050; E-7050; 

    IUPAC/Chemical Name: N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

    InChi Key: BWEYRDZIIMFBJR-UHFFFAOYSA-N

    InChi Code: InChI=1S/C33H37F2N7O4/c1-39-16-18-40(19-17-39)23-9-14-41(15-10-23)32(45)38-29-21-26(8-13-37-29)46-25-6-7-28(27(35)20-25)42(24-4-2-22(34)3-5-24)31(44)33(11-12-33)30(36)43/h2-8,13,20-21,23H,9-12,14-19H2,1H3,(H2,36,43)(H,37,38,45)

    SMILES Code: O=C(C1(C(N)=O)CC1)N(C2=CC=C(OC3=CC(NC(N4CCC(N5CCN(C)CC5)CC4)=O)=NC=C3)C=C2F)C6=CC=C(F)C=C6


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    In Vitro

    In vitro activity: In vitro studies indicate that 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 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.


    Kinase Assay: The phosphorylation status of c-Met and VEGFR-2 is detected by Western blot analysis. For c-Met, MKN45 cells are incubated with a serial dilution of E7050 in complete medium at 37 °C for 2 h. For VEGFR-2, HUVEC are starved with human endothelial serum free medium containing 0.5% FBS for 24 h. Subsequently HUVEC are incubated with a serial dilution of E7050 for 1 h and then incubated with 20 ng/mL of human VEGF for 5 min. Cells are lysed by lysis buffer (50 mM HEPES [pH 7.4], 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2, 1 mM EDTA [pH 8.0], 100 mM NaF, 1 mM phenylmethylsulfonyl fluoride 1 mM sodium orthovanadate, 10 μg/mL aprotinin, 50 μg/mL leupeptin, and 1 μg/mL pepstatin A). The resected tumor samples are homogenized with lysis buffer containing 25 mM β-glycerophosphate and 0.5% (v/v) phosphatase inhibitor cocktail 2 at 4 °C. Cellular debris is removed by centrifugation at 17 860g for 20 min at 4 °C. Aliquots of the supernatants containing 5-20 μg of protein are subjected to SDS-PAGE under reducing conditions. The proteins are then transferred onto PVDF membranes, blocked with TBS containing 0.05% Tween-20 and either 5% skim milk or 5% BSA. The membranes are probed with the following antibodies: anti-c-Met polyclonal antibody (C-28) and anti-VEGFR-2 polyclonal antibody (C-20); mouse anti-phosphotyrosine clone 4G10; and anti-VEGFR-2 polyclonal antibody, anti-phospho-VEGFR-2 (Tyr996) polyclonal antibody, and anti-phospho-c-Met (Tyr1234/1235) polyclonal antibody. Detection is performed using a Super Signal enhanced chemiluminescence kit. Immunoreactive bands are visualized by chemiluminescence with an Image Master-VDS-CL detection system. The intensity of each band is measured by using an image analyzer. 


    Cell Assay: Cells (1–3 × 103 cells/100 μL/well, MKN45, EBC-1, Hs746T, SNU-5, A549, SNU-1 and MKN74) 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. HUVEC (2 × 103 cells/well) are cultured for 3 days in medium containing HGF (30 ng/mL), VEGF (20 ng/mL), or basic fibroblast growth factor (bFGF) (20 ng/mL) together with serially diluted E7050.

    In Vivo In vivo studies using 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 E7050 (50–200 mg/kg) induces 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. In another xenograft model research, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells are more angiogenic than vector control tumors and shows resistance to ZD1839. E7050 alone inhibits angiogenesis and retards growth of Ma-1/HGF tumors. E7050 combined with ZD1839 induces marked regression of tumor growth.
    Animal model s.c. xenograft models
    Formulation & Dosage Dissolved in sterile distilled water; 50–200 mg/kg; p.o.
    References

    Cancer Sci. 2010 Jan;101(1):210-5; Clin Cancer Res. 2012 Mar 15;18(6):1663-71; Am J Pathol. 2012 Sep;181(3):1034-43.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Golvatinib (E7050)

    E7050 reverses HGF-induced resistance to next-generation EGFR-TKIs in H1975 cells. Clin Cancer Res. 2012 Mar 15;18(6):1663-71.

    Golvatinib (E7050)

    E7050 prevents the emergence of gefitinib-resistant HCC827 cells with amplified Met induced by continuous exposure to HGF. Clin Cancer Res. 2012 Mar 15;18(6):1663-71.

    Golvatinib (E7050)

    E7050 circumvents HGF-induced resistance when combined with gefitinib in vivo. Clin Cancer Res. 2012 Mar 15;18(6):1663-71.


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