Home Protein Tyrosine Kinase c-Met inhibitor - VEGFR inhibitor Golvatinib (E7050)

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Golvatinib (E7050) c-Met inhibitor

Cat.No.S2859

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

Chemical Structure

Molecular Weight: 633.69

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Quality Control

Batch: S285901 DMSO]20 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.78%
99.78

Chemical Information, Storage & Stability

Molecular Weight 633.69 Formula

C33H37F2N7O4

 Storage (From the date of receipt)
CAS No. 928037-13-2 Download SDF Storage of Stock Solutions

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

Solubility

In vitro
Batch:

DMSO : 20 mg/mL (31.56 mM)
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Water : Insoluble

Ethanol : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
c-Met [1]
14 nM
VEGFR2 [1]
16 nM
In vitro
In vitro studies indicate that Golvatinib (E7050) potently inhibits phosphorylation of both c-Met and VEGFR-2. It also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. [1] This compound 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. It also prevents the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. [2]
Kinase Assay
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 Golvatinib (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 this compound 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.
In vivo
Golvatinib (E7050) shows inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors in vivo, with strong suppression of tumor growth and angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of this compound (50–200 mg/kg) induces tumor regression and disappearance. In a peritoneal dissemination model, it demonstrates an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. [1] In another xenograft study, tumors produced by HGF-transfected Ma-1 (Ma-1/HGF) cells are more angiogenic than vector control tumors and show resistance to ZD1839. E7050 alone inhibits angiogenesis and retards growth of Ma-1/HGF tumors, and when combined with ZD1839, it induces marked regression of tumor growth. [3]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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