Foretinib

Foretinib (GSK1363089, XL880) is a novel MET and VEGFR2/KDR kinases inhibitor with an IC50 of 0.4 and 0.8 nM for MET and KDR, respectively. Foretinib (GSK1363089, XL880) inhibits HGF receptor family tyrosine kinases with an IC50 of 3 nM for Ron. Foretinib (GSK1363089, XL880) 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 (GSK1363089, XL880) exhibits modest activity against fibroblast growth factor receptor 1 and epidermal growth factor receptor and is inactive against 50 serine/threonine kinases, including cyclin-dependent kinases and protein kinase C isoforms. To delineate the cellular effect of foretinib (GSK1363089, XL880), VEGF- induced extracellular signal-regulated kinase phosphorylation was used to assess the effect of the compound on phosphorylation of KDR in human umbilical vein endothelial cells that resulted in an IC50 of 16 nM. Foretinib(GSK1363089, XL880) is the 1st orally available small molecule inhibitor of Met to enter the clinic and appears to be generally well tolerated. Anti-tumor activity has been observed and Foretinib may represent an active treatment option for patients with papillary renal-cell carcinoma.