2FB8

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

2FB8 の概要

• エントリーDOI: 10.2210/pdb2fb8/pdb
• 分子名称: B-Raf proto-oncogene serine/threonine-protein kinase, (1Z)-5-(2-{4-[2-(DIMETHYLAMINO)ETHOXY]PHENYL}-5-PYRIDIN-4-YL-1H-IMIDAZOL-4-YL)INDAN-1-ONE OXIME (3 entities in total)
• 機能のキーワード: kinase domain, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64734.83

構造登録者

Lougheed, J.C.,Lee, J.,Chau, D.C.,Stout, T.J. (登録日: 2005-12-08, 公開日: 2006-12-12, 最終更新日: 2024-02-14)

主引用文献

King, A.J.,Patrick, D.R.,Batorsky, R.S.,Ho, M.L.,Do, H.T.,Zhang, S.Y.,Kumar, R.,Rusnak, D.W.,Takle, A.K.,Wilson, D.M.,Hugger, E.,Wang, L.,Karreth, F.,Lougheed, J.C.,Lee, J.,Chau, D.,Stout, T.J.,May, E.W.,Rominger, C.M.,Schaber, M.D.,Luo, L.,Lakdawala, A.S.,Adams, J.L.,Contractor, R.G.,Smalley, K.S.,Herlyn, M.,Morrissey, M.M.,Tuveson, D.A.,Huang, P.S.
Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.
Cancer Res., 66:11100-11105, 2006

PubMed 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.

PubMed: 17145850
DOI: 10.1158/0008-5472.CAN-06-2554

実験手法

X-RAY DIFFRACTION (2.9 Å)