Plx-4032

PLX-4032 is a small-molecule B-Raf inhibitor for the potential treatment of malignant melanoma.PLX-4032 and its related analogs are highly potent inhibitors of B-Raf activity, with 3-fold selectivity for the V600E mutation over the wild-type kinase. In preclinical models, PLX-4032 and its analogs inhibited the growth of BRAFV600E-positive melanoma cell lines both in vitro and in vivo.(In Vitro):Vemurafenib (PLX4032) selectively blocks the RAF/MEK/ERK pathway in BRAF mutant cells. RG7204 is a potent inhibitor of proliferation in those expressing RAFV600E but not BRAFWT in 17 melanoma cell lines. Vemurafenib (RG7204) induces MEK and ERK phosphorylation at high concentrations in CHL-1 cells. Ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032.(In Vivo):Vemurafenib (PLX4032, 20, 25, 75 mg/kg, p.o.) causes dose-dependent inhibition of tumor growth, with higher exposures resulting in tumor regression of BRAF mutant xenografts. RG7204 (12.5, 25, and 75 mg/kg, p.o.) significantly inhibits tumor growth and induced tumor regression in mice bearing LOX tumor xenografts.