Lifirafenib (BGB-283) (C09-0935-875)

InformationLifirafenib (BGB-283, Beigene-283) potently inhibitsRAFfamily kinases andEGFRactivities in biochemical assays withIC50values of 23, 29 and 495 nM for the recombinant BRAFV600E kinase domain, EGFR and EGFR T790M/L858R mutant.TargetsWT A-RAF (Cell-free assay); C-RAF (Y340/341D) (Cell-free assay); BRAF(V600E) (Cell-free assay); EGFR (Cell-free assay); BRAF WT (Cell-free assay) 16546,1 nM; 7 nM; 23 nM; 29 nM; 32 nMIn vitroBGB-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 mutatiomplification. In BRAFV600E colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. It demonstrates selective cytotoxicity to cell lines harboring BRAFV600E or EGFR mutations. BGB-283 inhibits the EGF-induced EGFR autophosphorylation on Tyr1068 in A431 cells in a dose-dependent manner. In WiDr colorectal cancer cells, BGB-283 is shown to be able to inhibit the feedback activation of EGFR signaling and achieves sustained inhibition of pERK.In vivoBGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAFV600E mutation. BGB-283 is highly efficacious in BRAF(V600E) colorectal cancer xenograft models, including HT29, Colo205, 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 ERK1/2 and EGFR 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 MEK and ERK phosphorylation and DUSP6 expression in vivo when dosed repeatedly. There is no detectable difference on AKT phosphorylation.Cell Research(from reference)Cell lines：A375 cells Concentrations：0.03, 1, 10 μM Incubation Time：3 days. Specification: 0.99 Molecular Formula: C25H17F3N4O3 Molecular Weight: 478.42 PubChem CID: 89670174 Isomeric SMILES: C1CC(=O)NC2=NC=CC(=C21)OC3=CC4=C(C=C3)O[C@H]5[C@@H]4[C@@H]5C6=NC7=C(N6)C=C(C=C7)C(F)(F)F