2fb8

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{{STRUCTURE_2fb8| PDB=2fb8 | SCENE= }}
{{STRUCTURE_2fb8| PDB=2fb8 | SCENE= }}
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'''Structure of the B-Raf kinase domain bound to SB-590885'''
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===Structure of the B-Raf kinase domain bound to SB-590885===
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==Overview==
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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.
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==About this Structure==
==About this Structure==
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[[Category: Stout, T J.]]
[[Category: Stout, T J.]]
[[Category: Kinase domain]]
[[Category: Kinase domain]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 03:41:07 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 13:25:08 2008''

Revision as of 10:25, 27 July 2008

Image:2fb8.png

Template:STRUCTURE 2fb8

Structure of the B-Raf kinase domain bound to SB-590885

Template:ABSTRACT PUBMED 17145850

About this Structure

2FB8 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

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