Golvatinib (also known as E7050) is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family. c-Met and VEGFR-2 play important roles in tumor cell growth, migration and angiogenesis. Golvatinib (E7050) 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. In vitro, Golvatinib (E7050) circumvented 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. Golvatinib (E7050) plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells in the in vivo model. Golvatinib is currently under evaluation in a phase I clinical trial, it may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
| Cell Experiment | |
|---|---|
| Cell lines | MKN45, SNU-5, Hs746, TEBC-1, MKN74, SNU-1 and A549 cells line |
| Preparation method | Cell proliferation assay. Cells (1-3*103 cells/100 uL/well) were seeded on 96-well culture plates with various concentrations of E7050 and cultured for 3 days. Then, 10 uL of CCK-8 reagent was added to each well, and absorbance was measured at 450 nm compared with a reference measurement at 660 nm using a MTP-500 microplate reader (Corona Electric, Ibaraki, Japan). Proliferation assays using HUVEC were performed as described previously. Briefly, HUVEC (2*103 cells/well) were cultured for 3 days in medium containing HGF (30 ng/mL), VEGF (20 ng/mL) (R&D Systems), or basic fibroblast growth factor (bFGF) (20 ng/mL) (Wako Pure Chemicals, Osaka, Japan) together with serially diluted E7050. |
| Concentrations | 0~10 μM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | Nude mice bearing MKN45 (a), Hs746T (b), SNU-5 (c), or EBC-1 (d) tumors model |
| Formulation | saline |
| Dosages | 25, 50, 100 or 200mg/kg daily for15 days |
| Administration | oral |
| Molecular Weight | 633.69 |
| Formula | C33H37F2N7O4 |
| CAS Number | 928037-13-2 |
| Solubility (25°C) | DMSO 20 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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Capmatinib dihydrochloride hydrate is a potent, orally active, selective, ATP-competitive c-Met kinase inhibitor (IC50=0.13 nM) that inhibits the phosphorylation of c-MET, as well as downstream effector proteins of the c-MET pathway, such as ERK1/2, AKT, FAK, In addition, Capmatinib dihydrochloride hydrate effectively inhibited the proliferation and migration of c-Met-dependent tumor cells, induced apoptosis, and demonstrated antitumor activity in a mouse model of tumor. Capmatinib dihydrochloride hydrate is mainly metabolized by CYP3A4 and aldehyde oxidase. |
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