2FB8
Structure of the B-Raf kinase domain bound to SB-590885
Summary for 2FB8
| Entry DOI | 10.2210/pdb2fb8/pdb |
| Descriptor | 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) |
| Functional Keywords | kinase domain, transferase |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (By similarity): P15056 |
| Total number of polymer chains | 2 |
| Total formula weight | 64734.83 |
| Authors | Lougheed, J.C.,Lee, J.,Chau, D.C.,Stout, T.J. (deposition date: 2005-12-08, release date: 2006-12-12, Last modification date: 2024-02-14) |
| Primary citation | 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 Cited by 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: 17145850DOI: 10.1158/0008-5472.CAN-06-2554 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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