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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
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,doi
10.1158/0008-5472.CAN-06-2554subject
Has Abstractpub_date
2006-12-01 00:00:00pages
11100-5issue
23eissn
0008-5472issn
1538-7445pii
66/23/11100journal_volume
66pub_type
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