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2fb8
From Proteopedia
Structure of the B-Raf kinase domain bound to 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.
Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885., King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, Karreth F, Lougheed JC, Lee J, Chau D, Stout TJ, May EW, Rominger CM, Schaber MD, Luo L, Lakdawala AS, Adams JL, Contractor RG, Smalley KS, Herlyn M, Morrissey MM, Tuveson DA, Huang PS, Cancer Res. 2006 Dec 1;66(23):11100-5. PMID:17145850
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
2FB8 is a 2 chains structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM, Hugger E, Wang L, Karreth F, Lougheed JC, Lee J, Chau D, Stout TJ, May EW, Rominger CM, Schaber MD, Luo L, Lakdawala AS, Adams JL, Contractor RG, Smalley KS, Herlyn M, Morrissey MM, Tuveson DA, Huang PS. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006 Dec 1;66(23):11100-5. PMID:17145850 doi:66/23/11100
Page seeded by OCA on Mon Feb 16 11:24:39 2009
