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Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885
- Source :
- Cancer Research. 66:11100-11105
- Publication Year :
- 2006
- Publisher :
- American Association for Cancer Research (AACR), 2006.
-
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. (Cancer Res 2006; 66(23): 11100-5)
- Subjects :
- Models, Molecular
Proto-Oncogene Proteins B-raf
Cancer Research
Protein Conformation
Blotting, Western
Mice, Nude
Biology
Crystallography, X-Ray
medicine.disease_cause
Mice
Cell Movement
Mutant protein
Cell Line, Tumor
Neoplasms
Gene expression
medicine
Animals
Humans
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Protein Kinase Inhibitors
Alleles
Cell Proliferation
Molecular Structure
Kinase
Imidazoles
Xenograft Model Antitumor Assays
Molecular biology
Blot
Oncology
Protein kinase domain
Mechanism of action
Cell culture
Mutation
Cancer research
Female
medicine.symptom
Crystallization
Carcinogenesis
HT29 Cells
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....a0c07ce13bb3eaa1a428ffcbce4a6d18