Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. Foretinib (XL880, GSK1363089) inhibits HGF receptor family tyrosine kinases with an IC50 of 3 nM for Ron. Foretinib (XL880, GSK1363089) also inhibits KDR, Flt-1, and Flt-4 with IC50 of 0.9, 6.8 and 2.8 nM, respectively. In addition, EXEL-2880 inhibits members of the platelet-derived growth factor receptor family and the angiopoietin-1 receptor Tie-2. Foretinib (XL880, GSK1363089) is the 1st orally available small molecule inhibitor of Met to enter the clinic and appears to be generally well tolerated.
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Source | J Cancer (2017). Figure 2. Foretinib |
| Method | Apoptosis assay | |
| Cell Lines | ESCC cells | |
| Concentrations | 0.1 and 0.5 μM | |
| Incubation Time | 24h | |
| Results | The results demonstrated that foretinib significantly enhances apoptosis induced by ionizing radiation. |
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Source | J Cancer (2017). Figure 1. Foretinib |
| Method | Cell viability assay | |
| Cell Lines | ECA-109 and TE-13 cells | |
| Concentrations | 0.1 and 0.5 μM | |
| Incubation Time | 24h and 48h | |
| Results | Foretinib treatment (0.1 and 0.5 μM) combined ionizing radiation significantly shifted the dose-survival curves compared with the control group. |
| Cell Experiment | |
|---|---|
| Cell lines | B16F10 cells |
| Preparation method | HGF-induced migration assay. B16F10 cells (2 *105) were seeded onto 0.8 Am membranes in the top chamber of a 96-well Transwell plate in DMEM containing a serial dilution of EXEL-2880 and 0.1% FBS. DMEM containing HGF (50 ng/mL), 0.2% FBS, and EXEL-2880(foretinib) was added to the bottom chamber, and after 24 h, the medium was removed and Accutase (ISC BioExpress) was added to the bottom chamber. After 30 min, cells were transferred to a V-bottomed 96-well plate, centrifuged, and resuspended in HBSS containing 2 mg/mL calcein-AM (Molecular Probes). After incubation for 30 min, cells were transferred into a black 96-well plate. Fluorescence emission was measured at 480 nm using an excitation wavelength of 520 nm and imaged with a fluorescence microscope. |
| Concentrations | 14, 41, 123nM |
| Incubation time | 24h |
| Animal Experiment | |
|---|---|
| Animal models | ligand (e.g., HGF or VEGF)–induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung |
| Formulation | 0.9% saline |
| Dosages | 100 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 632.65 |
| Formula | C34H34F2N4O6 |
| CAS Number | 849217-64-7 |
| Solubility (25°C) | DMSO 90 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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