Golvatinib (E7050)

For research use only.

Catalog No.S2859

5 publications

CAS No. 928037-13-2

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.

Selleck's Golvatinib (E7050) has been cited by 5 publications

Cell, 2019, 178(6):1478-1492

PubMed: 31474362 ( click the link to review the publication )

Nephron, 2020, 1-12

PubMed: 32799196 ( click the link to review the publication )

Cancer Sci, 2017, 108(7):1378-1385

PubMed: 28474864 ( click the link to review the publication )

Mol Cancer Ther, 2017, 16(3):506-515

PubMed: 28138027 ( click the link to review the publication )

Cancer Med, 2017, 6(12):2972-2983

PubMed: 29125233 ( click the link to review the publication )

3 Customer Reviews

PC-9/LMC-GR cells (2 × 105 cells/well) were incubated in 6-well plates with various concentrations of gefitinib with or without crizotinib (1 μmol/L) or golvatinib (1 μmol/L) for 1 hour. Cell lysate were obtained and subjected to immunoblotting with antibodies toward the indicated molecules.

Mol Cancer Ther, 2017, 16(3):506-515. Golvatinib (E7050) purchased from Selleck.

B, PC-9/LMC-GR cells (2 × 105 cells/well) were incubated in 6-well plates with various concentrations of gefitinib with or without crizotinib (1 μmol/L) or golvatinib (1 μmol/L) for 1 hour. Cell lysate were obtained and subjected to immunoblotting with antibodies toward the indicated molecules.

Mol Cancer Ther, 2017, 16(3):506-515. Golvatinib (E7050) purchased from Selleck.
SBC-5, DMS273, and DMS273-G3H cells were treated with either 1 lM crizotinib or golvatinib for 2 h. Cell lysates were evaluated for protein expression by Western blot analysis. Three independent experiments were carried out, and a representative result is shown. p, phosphorylated.

Cancer Sci, 2017, 108(7):1378-1385. Golvatinib (E7050) purchased from Selleck.

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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

Kinase Assay:^[1]	- Collapse 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]	- Collapse 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. (Only for Reference)
Animal Research:^[1]	- Collapse Animal Models: Subcutaneous xenograft models Dosages: 50–200 mg/kg Administration: orally once a day (Only for Reference)

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.	30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download Golvatinib (E7050) SDF

Molecular Weight	633.69
Formula	C₃₃H₃₇F₂N₇O₄
CAS No.	928037-13-2
Storage	3 years-20°C powder 2 years-80°C in solvent
Synonyms	N/A
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

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Method for preparing DMSO master liquid: ： mg drug pre-dissolved in μL DMSO (Master liquid concentration mg/mL， Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation：Take DMSO master liquid, next addμL PEG300， mix and clarify, next addμL Tween 80，mix and clarify, next add μL ddH₂O，mix and clarify.

Note：1.Please make sure the liquid is clear before adding the next solvent.
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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2020-09-01)

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	Completed	Drug: E7050\|Drug: Lenvatinib	Advanced Solid Tumors	Eisai Inc.	October 13 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

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c-Met Signaling Pathway Map

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Golvatinib (E7050)