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Purity: ≥98%
Golvatinib (formerly E-7050) is an orally bioavailable dual c-Met and VEGFR-2 inhibitor with potential antineoplastic activity. It has IC50 values of 14 nM and 16 nM for c-Met and VEGFR-2 inhibition, respectively, and has no effect on bFGF-stimulated HUVEC growth (up to 1000 nM). By attaching to and blocking the functions of both c-Met and VEGFR-2, which are upregulated in a variety of tumors and have significant roles in the growth, migration, and angiogenesis of tumor cells, golvatinib exhibits strong anti-proliferative activity in vitro and strong antitumor efficacy in vivo.
| Targets |
VEGFR2 (IC50 = 16 nM); c-Met (IC50 = 14 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Western blot analysis is used to detect the phosphorylation status of VEGFR-2 and c-Met. MKN45 cells are incubated with a serial dilution of E7050 in full medium at 37 °C for two hours in order to detect c-Met. For 24 hours, HUVEC are starved with human endothelial serum free medium containing 0.5% FBS in order to test for VEGFR-2. The next step involves incubating HUVEC for one hour with a serial dilution of E7050 and for five minutes with 20 ng/mL of human VEGF. 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, and 1 mM phenylmethylsulfonyl fluoride) is used to lyse the cells. 1 mM sodium orthovanadate, 10 μg/mL aprotinin, 50 μg/mL leupeptin, and 1 μg/mL pepstatin A). Tumor samples that have been removed are homogenized using lysis buffer that contains 0.5% (v/v) phosphatase inhibitor cocktail 2 and 25 mM β-glycerophosphate at 4 °C. Centrifugation at 17 860 g for 20 min at 4 °C removes cellular debris. Supernatants aliquots containing 5–20 μg of protein are run through reducing conditions on SDS-PAGE. After that, the proteins are put onto PVDF membranes and blocked with TBS that has 0.05% Tween-20 and either 5% BSA or 5% skim milk in it. The following antibodies are used to probe the membranes: mouse anti-phosphotyrosine clone 4G10; anti-c-Met polyclonal antibody (C-28) and anti-VEGFR-2 polyclonal antibody (C-20); anti-phospho-VEGFR-2 (Tyr996) polyclonal antibody, and anti-phospho-c-Met (Tyr1234/1235) polyclonal antibody. Using an enhanced chemiluminescence kit from Super Signal, detection is done. A chemiluminescence detection system called Image Master-VDS-CL is used to see immunoreactive bands. Using an image analyzer, the intensity of each band is determined.
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| Cell Assay |
On 96-well culture plates, cells (1–3 × 103 cells/100 μL/well) are seeded with varying concentrations of E7050 and cultured for three days. After adding 10 μL of WST-8 reagent to each well, an MTP-500 microplate reader is used to measure absorbance at 450 nm and compare it to a reference measurement at 660 nm. For three days, HUVEC (2 × 103 cells/well) are cultured in a medium containing serially diluted E7050 along with HGF (30 ng/mL), VEGF (20 ng/mL), or basic fibroblast growth factor (bFGF) (20 ng/mL).
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| Animal Protocol |
Mice: Golvatinib (25, 50, 100, or 200 mg/kg) or vehicle alone as a control is given once daily to naked mice with tumors containing MKN45, Hs746T, SNU-5, or EBC-1. On the days indicated (0–15 days), the tumor volume is measured with calipers.
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| References | ||
| Additional Infomation |
Golvatinib is an aromatic ether.
Golvatinib has been investigated for the treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck. Golvatinib is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosine kinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and 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. c-Met and VEGFR-2 are upregulated in a variety of tumor cell types and play important roles in tumor cell growth, migration and angiogenesis. |
| Molecular Formula |
C33H37F2N7O4
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| Molecular Weight |
633.69
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| Exact Mass |
633.287
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| Elemental Analysis |
C, 62.55; H, 5.89; F, 6.00; N, 15.47; O, 10.10
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| CAS # |
928037-13-2
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| Related CAS # |
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| PubChem CID |
16118392
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| Appearance |
white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
867.5±65.0 °C at 760 mmHg
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| Flash Point |
478.5±34.3 °C
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| Vapour Pressure |
0.0±3.3 mmHg at 25°C
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| Index of Refraction |
1.671
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| LogP |
2.03
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
46
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| Complexity |
1060
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(N1CCC(N2CCN(C)CC2)CC1)NC1C=C(OC2C=C(F)C(NC(C3(CC3)C(NC3C=CC(F)=CC=3)=O)=O)=CC=2)C=CN=1
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| InChi Key |
UQRCJCNVNUFYDX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H37F2N7O4/c1-40-16-18-41(19-17-40)24-9-14-42(15-10-24)32(45)39-29-21-26(8-13-36-29)46-25-6-7-28(27(35)20-25)38-31(44)33(11-12-33)30(43)37-23-4-2-22(34)3-5-23/h2-8,13,20-21,24H,9-12,14-19H2,1H3,(H,37,43)(H,38,44)(H,36,39,45)
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| Chemical Name |
1-N'-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
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| Synonyms |
E 7050; Golvatinib; E7050; E-7050
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5781 mL | 7.8903 mL | 15.7806 mL | |
| 5 mM | 0.3156 mL | 1.5781 mL | 3.1561 mL | |
| 10 mM | 0.1578 mL | 0.7890 mL | 1.5781 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01271504 | Completed | Drug: Sorafenib | Hepatocellular Carcinoma | Eisai Inc. | July 19, 2011 | Phase 1 Phase 2 |
| NCT01332266 | Completed | Drug: E7050 Drug: Cetuximab |
Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck |
Eisai Inc. | September 19, 2011 | Phase 1 Phase 2 |
| NCT01355302 | Terminated | Drug: E7050 Drug: cisplatin |
Advanced or Metastatic Solid Tumors Previously Untreated Gastric Cancer |
Eisai 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 |
E7050 reverses HGF-induced resistance to next-generation EGFR-TKIs in H1975 cells. Clin Cancer Res. 2012 Mar 15;18(6):1663-71. |
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. |
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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