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PLX-4720

PLX4720 is a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele.  

Current developer:    Plexxikon, Inc.

PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors. see http://www.ncbi.nlm.nih.gov/pubmed/18287029.

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7. Tsai James; Lee John T; Wang Weiru; Zhang Jiazhong; Cho Hanna; Mamo Shumeye; Bremer Ryan; Gillette Sam; Kong Jun; Haass Nikolas K; Sproesser Katrin; Li Ling; Smalley Keiran S M; Fong Daniel; Zhu Yong-Liang; Marimuthu Adhirai; Nguyen Hoa; Lam Billy; Liu Jennifer; Cheung Ivana; Rice Julie; Suzuki Yoshihisa; Luu Catherine; Settachatgul Calvin; Shellooe Rafe; Cantwell John; Kim Sung-Hou; Schlessinger Joseph; Zhang Kam Y J; West Brian L; Powell Ben; Habets Gaston; Zhang Chao; Ibrahim Prabha N; Hirth Peter; Artis Dean R; Herlyn Meenhard; Bollag Gideon Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America (2008), 105(8), 3041-6.