Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.
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.
King
Alastair J
AJ
Department of Oncology, MMPD CEDD, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA.
Patrick
Denis R
DR
Batorsky
Roberta S
RS
Ho
Maureen L
ML
Do
Hieu T
HT
Zhang
Shu Yun
SY
Kumar
Rakesh
R
Rusnak
David W
DW
Takle
Andrew K
AK
Wilson
David M
DM
Hugger
Erin
E
Wang
Lifu
L
Karreth
Florian
F
Lougheed
Julie C
JC
Lee
Jae
J
Chau
David
D
Stout
Thomas J
TJ
May
Earl W
EW
Rominger
Cynthia M
CM
Schaber
Michael D
MD
Luo
Lusong
L
Lakdawala
Ami S
AS
Adams
Jerry L
JL
Contractor
Rooja G
RG
Smalley
Keiran S M
KS
Herlyn
Meenhard
M
Morrissey
Michael M
MM
Tuveson
David A
DA
Huang
Pearl S
PS
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
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