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.

BGB-283 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.BGB-283 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, BGB-283 inhibits the EGF-induced EGFR autophosphorylation on Tyr1068 in a dose-dependent manner. In WiDr colorectal cancer cells, BGB-283 inhibits the feedback activation of EGFR signaling and achieves sustained inhibition of pERK[1]

The treatment of BGB-283 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. BGB-283 has high efficacy in BRAF(V600E) colorectal cancer xenograft models, including Colo205, HT29, and two primary tumor xenografts harboring BRAFV600E mutation. In addition, BGB-283 shows compelling efficacy in a WiDr xenograft model where EGFR reactivation is shown to be induced upon BRAF inhibition. BGB-283 induces tumor regression in HCC827 but not in A431 xenograft. BGB-283 inhibits phosphorylation of both EGFR and ERK1/2 and displays potent antitumor activity in WiDr tumor xenografts. BGB-283 does not induce EGFR feedback activation as reported for vemurafenib. BGB-283 potently inhibits DUSP6 expression, ERK and MEK phosphorylation in vivo when dosed repeatedly. There is no detectable difference on AKT phosphorylation[1].