title: Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.
abstract: BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. 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.
authors.affiliation: Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.
authors.forename: James
authors.initials: J
authors.lastname: Tsai
authors.forename: John T
authors.initials: JT
authors.lastname: Lee
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.forename: Shumeye
authors.initials: S
authors.lastname: Mamo
authors.forename: Ryan
authors.initials: R
authors.lastname: Bremer
authors.forename: Sam
authors.initials: S
authors.lastname: Gillette
authors.forename: Jun
authors.initials: J
authors.lastname: Kong
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.forename: Katrin
authors.initials: K
authors.lastname: Sproesser
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Daniel
authors.initials: D
authors.lastname: Fong
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Zhu
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.forename: Billy
authors.initials: B
authors.lastname: Lam
authors.forename: Jennifer
authors.initials: J
authors.lastname: Liu
authors.forename: Ivana
authors.initials: I
authors.lastname: Cheung
authors.forename: Julie
authors.initials: J
authors.lastname: Rice
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Catherine
authors.initials: C
authors.lastname: Luu
authors.forename: Calvin
authors.initials: C
authors.lastname: Settachatgul
authors.forename: Rafe
authors.initials: R
authors.lastname: Shellooe
authors.forename: John
authors.initials: J
authors.lastname: Cantwell
authors.forename: Sung-Hou
authors.initials: SH
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.forename: Ben
authors.initials: B
authors.lastname: Powell
authors.forename: Gaston
authors.initials: G
authors.lastname: Habets
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Peter
authors.initials: P
authors.lastname: Hirth
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004926:Escherichia coli; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009857:Oncogenes / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf