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Golvatinib (E7050)

Catalog No.S2859

For research use only.

Golvatinib (E7050) is a dual c-Met and VEGFR-2 inhibitor with IC50 of 14 nM and 16 nM, does not inhibit bFGF-stimulated HUVEC growth (up to 1000 nM). Phase 1/2.

CAS No. 928037-13-2

Selleck's Golvatinib (E7050) has been cited by 6 Publications

3 Customer Reviews

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c-Met Signaling Pathway Map

Biological Activity

Description

Golvatinib (E7050) is a dual c-Met and VEGFR-2 inhibitor with IC50 of 14 nM and 16 nM, does not inhibit bFGF-stimulated HUVEC growth (up to 1000 nM). Phase 1/2.

Targets

c-Met ^[1]	VEGFR2 ^[1]
14 nM	16 nM

In vitro

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. ^[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]

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. ^[1] 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. ^[3]

Protocol (from reference)

Kinase Assay:^[1]	Western blot analysis: 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 Research:^[1]	Cell lines: MKN45, EBC-1, Hs746T, SNU-5, A549, SNU-1 and MKN74 Concentrations: 5-5000 nM Incubation Time: 3 days Method: Cells (1–3 × 10³ 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. 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.
Animal Research:^[1]	Animal Models: Subcutaneous xenograft models Dosages: 50–200 mg/kg Administration: orally once a day

References	[1] Nakagawa T et al. Cancer Sci, 2010, 101(1), 210-215. [2] Wang W et al. Clin Cancer Res, 2012, 18(6), 1663-1671. [3] Takeuchi S et al. Am J Pathol, 2012, 181(3), 1034-1043.

References

Solubility (25°C)

In vitro	DMSO	20 mg/mL (31.56 mM)
	Water	Insoluble
	Ethanol	Insoluble
In vivo	Add solvents to the product individually and in order (Data is from Selleck tests instead of citations): 30% propylene glycol, 5% Tween 80, 65% D5W For best results, use promptly after mixing. Click to purchase: Tween 80	30 mg/mL

Chemical Information

Molecular Weight	633.69
Formula	C₃₃H₃₇F₂N₇O₄
CAS No.	928037-13-2
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	CN1CCN(CC1)C2CCN(CC2)C(=O)NC3=NC=CC(=C3)OC4=CC(=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

Download Golvatinib (E7050) SDF

In vivo Formulation Calculator (Clear solution)

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Molarity Calculator

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Clinical Trial Information

NCT Number	Recruitment	Interventions	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT01355302	Terminated	Drug: E7050\|Drug: cisplatin\|Drug: capecitabine	Advanced or Metastatic Solid Tumors\|Previously Untreated Gastric Cancer	Eisai Inc.\|Quintiles Inc.	November 2011	Phase 1\|Phase 2
NCT01433991	Terminated	Drug: Golvatinib\|Drug: Lenvatinib	Advanced Solid Tumors	Eisai Inc.	October 13 2011	Phase 1\|Phase 2
NCT01332266	Completed	Drug: E7050\|Drug: Cetuximab	Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck	Eisai Inc.\|PharmaBio Development Inc.	September 19 2011	Phase 1\|Phase 2
NCT01271504	Completed	Drug: Sorafenib	Hepatocellular Carcinoma	Eisai Inc.\|PharmaBio Development Inc.	July 19 2011	Phase 1\|Phase 2
NCT02533102	Completed	Drug: E7050	Healthy Subjects	Eisai Limited\|Eisai Inc.	November 2010	Phase 1
NCT00921869	Completed	Drug: E7050	Solid Tumors	Eisai Co. Ltd.\|Eisai Inc.	October 2009	Phase 1

(data from https://clinicaltrials.gov, updated on 2022-01-17)

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

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