PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, denes a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-RafV600E kinase compared with a broad spectrum of other kinases and potent cytotoxic effects are also exclusive to cells bearing the V600E allele (GI50<1.7uM, while other wild cell GI50>10uM).Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-RafV600E -bearing tumor cell lines but not in cells lacking oncogenic B-Raf.In B-RafV600E -dependent tumor xenograft models, orally dosed PLX4720 causes signi cant tumor growth delays, including tumor regressions, without evidence of toxicity. |
