The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. Among them, B-RAF is the most frequently mutated protein kinase in human cancers. Encorafenib is a potent and selective B-RafV600E inhibitor, with no significant activity observed against a panel of 100 kinases (IC50>900nM). Encorafenib suppressed p-ERK with EC50 value of 3nM as well as led to potent inhibition of proliferation with EC50 value of 4nM in A375 cells (B-RafV600E), and did not inhibit proliferation of >400 cell lines expressing wild-type BRAF. Encorafenib showed good pharmacodynamics as single dose at 6mg/kg resulting in strong (75%) and sustained (>24h) decrease in p-MEK in PK/PD studies. Consistent with the in vitro data, Encorafenib can induce tumor regression in multiple BRAF mutant human tumor xenograft models grown in immune compromised mice and rats at doses as low as 1mg/kg, but inactive against BRAF wild-type tumors at doses up to 300 mg/kg bid[1].
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