title: Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.
abstract: Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor.
authors.affiliation: Department of Oncology, MMPD CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: King
authors.forename: Denis R
authors.initials: DR
authors.lastname: Patrick
authors.forename: Roberta S
authors.initials: RS
authors.lastname: Batorsky
authors.forename: Maureen L
authors.initials: ML
authors.lastname: Ho
authors.forename: Hieu T
authors.initials: HT
authors.lastname: Do
authors.forename: Shu Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Takle
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Erin
authors.initials: E
authors.lastname: Hugger
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.forename: Florian
authors.initials: F
authors.lastname: Karreth
authors.forename: Julie C
authors.initials: JC
authors.lastname: Lougheed
authors.forename: Jae
authors.initials: J
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Chau
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Stout
authors.forename: Earl W
authors.initials: EW
authors.lastname: May
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rominger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaber
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.forename: Ami S
authors.initials: AS
authors.lastname: Lakdawala
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Adams
authors.forename: Rooja G
authors.initials: RG
authors.lastname: Contractor
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Pearl S
authors.initials: PS
authors.lastname: Huang
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003460:Crystallization; D018360:Crystallography, X-Ray; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; C508204:SB-590885; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases