In vitro
As a small-molecule kinase inhibitor Foretinib (XL880, EXEL-2880, GSK1363089), is that targets members of the HGF and VEGF receptor tyrosine kinase families, KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Foretinib (XL880, EXEL-2880, GSK1363089) inhibits Met and VEGF receptor 2 (KDR) by deeply bounding in the Met kinase active site cleft.Foretinib (XL880, EXEL-2880, GSK1363089) inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation.
In vivo
Foretinib (XL880, EXEL-2880, GSK1363089) may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors. Foretinib (XL880, EXEL-2880, GSK1363089) prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. Foretinib (XL880, EXEL-2880, GSK1363089) prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. These effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis.In gastric cancer cell lines, foretinib (XL880, EXEL-2880, GSK1363089) inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. And MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib (XL880, EXEL-2880, GSK1363089). In ovarian cancer xenograft mouse models using human ovarian cancer cell lines, treatment with foretinib(XL880, EXEL-2880, GSK1363089) prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. Foretinib (XL880, EXEL-2880, GSK1363089) are involved in inhibition of c-Met activation and downstream signaling, reduction of ovarian cancer cell adhesion, a block in migration and invasion, reduced proliferation mediated by a G(2)-M cell-cycle arrest, and induction of anoikis.
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