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.
|Source||J Cancer (2017). Figure 2. Foretinib|
|Cell Lines||ESCC cells|
|Concentrations||0.1 and 0.5 μM|
|Results||The results demonstrated that foretinib significantly enhances apoptosis induced by ionizing radiation.|
|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 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|
|Animal models||ligand (e.g., HGF or VEGF)–induced receptor phosphorylation of Met in liver and Flk-1/KDR in lung|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO 93 mg/mL|
Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
Seiwert T et al. Invest New Drugs. 2012 Aug 24. PMID: 22918720.
Foretinib demonstrates anti-tumor activity and improves overall survival in preclinical models of hepatocellular carcinoma.
Huynh H et al. Angiogenesis. 2012 Mar;15(1):59-70. PMID: 22187171.
Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks.
Kataoka Y et al. Invest New Drugs. 2012 Aug;30(4):1352-60. PMID: 21655918.
Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis.
Zillhardt M et al. Clin Cancer Res. 2011 Jun 15;17(12):4042-51. PMID: 21551255.
Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells.
Liu L et al. Mol Cancer Ther. 2011 Mar;10(3):518-30. PMID: 21252284.
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Savolitinib (volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.
AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor.
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