Lifirafenib (Beigene-283) is a potent inhibitor of RAF family kinases and EGFR in biochemical assays with IC50 of 23, 29 and 495 nM for the recombinant BRAFV600E kinase domain, EGFR and EGFR T790M/L858R mutant respectively.

B-Raf (V600E):23 nM, EGFR:29 nM, EGFR (L858R/T790M):495 nM (IC50)

Lifirafenib potently inhibits BRAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAFV600E and EGFR mutation/amplification.Lifirafenib effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation，in BRAFV600E colorectal cancer cell lines. It demonstrates selective cytotoxicity to cell lines harboring BRAFV600E or EGFR mutations. In A431 cells, Lifirafenib inhibits the EGF-induced EGFR autophosphorylation on Tyr1068 in a dose-dependent manner. In WiDr colorectal cancer cells, Lifirafenib inhibits the feedback activation of EGFR signaling and achieves sustained inhibition of pERK[1]

The treatment of Lifirafenib leads to tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAFV600E mutation in a dose-dependent manner. Lifirafenib has high efficacy in BRAF(V600E) colorectal cancer xenograft models, including Colo205, HT29, and two primary tumor xenografts harboring BRAFV600E mutation. In addition, Lifirafenib shows compelling efficacy in a WiDr xenograft model where EGFR reactivation is shown to be induced upon BRAF inhibition. Lifirafenib induces tumor regression in HCC827 but not in A431 xenograft. Lifirafenib inhibits phosphorylation of both EGFR and ERK1/2 and displays potent antitumor activity in WiDr tumor xenografts. Lifirafenib does not induce EGFR feedback activation as reported for vemurafenib. Lifirafenib potently inhibits DUSP6 expression, ERK and MEK phosphorylation in vivo when dosed repeatedly. There is no detectable difference on AKT phosphorylation[1].