Foretinib, also known as EXEL-2880, XL880, and GSK1363089, is a small-molecule inhibitor of the hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinase families. Foretinib inhibited receptor tyrosine kinases (RTKs) in vitro with IC50 values of 0.4nM for Met and 3nM for Ron. It inhibited cellular Met with IC50 values of 23nM in PC-3 prostate cells and 21nM in murine B16F10 melanoma cells. It also reduced tumor cell migration, invasion, and endothelial tubule formation. Foretinib had cytotoxic activities against a broad panel of cell lines. It also blocked lung metastasis after the implantation of B16F10 solid tumors in mice. MET-amplified tumor lines with HER1 or HER2 amplification are more sensitive to the combination of foretinib with lapatinib or erlotinib. MET-overexpressing tumor cell lines with HER1 or HER2 amplification are less sensitive to lapatinib or erlotinib in the presence of HGF. Foretinib can reverse the effect of HGF on lapatinib or erlotinib sensitivity in these cells. Foretinib inhibits tumorigenesis and blocks invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions including inducing anoikis (anchorage-dependent programmed cell death) and inhibiting (1) c-Met activation and downstream signaling, (2) ovarian cancer cell adhesion, (3) migration and invasion, and (4) proliferation. Foretinib potently block multiple RTKs, including VEGF receptor and the receptor of HGF c-Met. Inhibition of c-Met and functionally related kinases intensifies the effects of VEGF receptor blockade, which leads to regression of tumor vasculature. Foretinib caused mitotic catastrophe in chronic myelogenous leukemia cells and other cell lines by JNK-dependent inhibition of Plk1 expression and induced apoptosis via a caspase 2-mediated mechanism. Foretinib had cytotoxic effects against gastric cancer cells harboring MET and FGFR2 amplification. It exerted its cytotoxic effects by blocking inter-RTK signaling networks with MET or FGFR2 at their center. Solubility: Soluble in DMSO at 150mg/mL, ethanol at 5mg/mL with warming, very poorly soluble in water, maximum solubility in plain water is estimated to be about 5-10uM, buffers, serum, or other additives may increase or decrease the aqueous solubility. Storage and Stability: Lyophilized powder may be stored at -20C. Stable for 6 months at -20C. Reconstitute with DMSO. Aliquot to avoid repeated freezing and thawing. Store at -20C. For maximum recovery of product, centrifuge the original vial after thawing and prior to removing the cap.
Molecular Weight:
632.65
Purity:
HPLC: ~99% TLC: ~99%
Form:
Supplied as a white to off-white crystalline solid.
CAS Number:
[849217-64-7]
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