The protein product of the MET proto-oncogene, c-Met, a receptor tyrosine kinase (RTK), is a prototype for the c-Met RTK subfamily and is activated by the ligand hepatocyte growth factor (HGF; scatter factor). Activation of the HGF/c‐Met pathway causes tumor progression, invasion, and metastasis[3]. Moreover, the c-Met signaling pathway engages with other pathways, including that of the EGFR/human EGFR/MAPK/ERK pathway and can also promote angiogenesis through interaction with the VEGF and VEGF receptor (VEGFR) pathway. In addition, c-Met signaling can downregulate the antiangiogenic thrombospondin-1 and upregulate VEGF and upregulation of HGF and c-Met occurs after VEGF inhibition. Golvatinib (E7050, Eisai) is a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family, as well as c-Kit and Ron, with an IC50 for c-Met of 0.001 μM[4]. E7050 inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2 and inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-Met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In a vitro study, MKN45 (gastric), SNU-5 (gastric), Hs746T (gastric), EBC-1 (lung), MKN74 (gastric), SNU-1 (gastric), A549 (lung) cell lines were treated with c-Met nonselective inhibitor E7050 at a dose ranging in 50-200 mg/kg to induce tumor regression and disappearance, indicating that E7050 is an efficient inhibitor of c-Met by inhibited phosphorylation of c-Met in tumors. In a vivo study, After different tumor cells were implanted subcutaneously (s.c.) into the mice respectively, E7050 was administered orally once a day at dose ranging from 25 mg/kg to 200 mg/kg for 8 to 15 days, suggesting that E7050 showed inhibition of the phosphorylation of c-Met in tumors, and strong inhibition of tumor growth and tumor angiogenesis. In a peritoneal dissemination model, MKN45 cells were inoculated intraperitoneally into nude mice and treated with E7050 at dose ranging from 25 mg/kg to 100 mg/kg for 6 days. E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. The results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer[3].
作用机制
Golvatinib binds to the MET enzyme with a 2-aminopyridine hinge binder.
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