PLX7904 is a potent and selective paradox-breaker RAF inhibitor. PLX7904 efficiently inhibits activation of ERK1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK1/2 in mutant RAS-expressing cells. Importantly, it inhibits ERK1/2 phosphorylation in mutant BRAF melanoma cells with acquired resistance to Vemurafenib/PLX4720 that is mediated by a secondary mutation in NRAS. Consistent with ERK1/2 reactivation driving the re-acquisition of malignant properties, PLX7904 promotes apoptosis and inhibits entry into S phase and anchorage-independent growth in mutant N-RAS-mediated Vemurafenib-resistant cells. MW: 512.54. Purity ≥98% by HPLC