The overexpression and activation of the Met receptor and its ligand HGF (hepatocyte growth factor) are associated with a wide variety of human malignancies, as well as the tumor invasion. Tepotinib is a selective c-Met inhibitor with IC50 value of 3nM (measured by kinase activity), over 200-fold against IRAK4, TrkA, Axl, IRAK1, Mer, TrkB and Ron. Exposure to Tepotinib resulted in inhibition of HGF-induced c-Met phosphorylation with IC50 of 6nM in A549 cells and a significant reduction of c-Met–constitutive phosphorylation with IC50 of 9nM in EBC-1 cells. The suppression of phosphorylation of the c-Met pathway, including Gab-1, Akt and Erk1/2, can also be observed. This kinase inhibition can also be observed in in vivo study as a single dose of 30mg/kg Tepotinib caused inhibition of c-Met auto-phosphorylation both in tumors derived from Hs746T xenograft mice, along with decreased cyclin D1 and inducing p27 expression, within 48h. As prediction, daily administration at dose of 6mg/kg significantly inhibited tumor growth in mice bearing human HGF-dependent pancreatic carcinoma cell line KP-4, while suppressed tumor growth at dose of 15mg/kg. In another model mice bearing subcutaneous tumors derived from the HGF-independent human lung cancer cell line EBC-1, the tumor growth by Tepotinib can be observed at dose of 25 or 50mg/kg, when the tumor suppression can be observed at dose of 200mg/kg[1].
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