Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 23; pp. 11100 - 11105
• Main Authors: KING, Alastair J, PATRICK, Denis R, HUGGER, Erin, LIFU WANG, KARRETH, Florian, LOUGHEED, Julie C, LEE, Jae, CHAU, David, STOUT, Thomas J, MAY, Earl W, ROMINGER, Cynthia M, SCHABER, Michael D, BATORSKY, Roberta S, LUSONG LUO, LAKDAWALA, Ami S, ADAMS, Jerry L, CONTRACTOR, Rooja G, SMALLEY, Keiran S. M, HERLYN, Meenhard, MORRISSEY, Michael M, TUVESON, David A, HUANG, Pearl S, HO, Maureen L, DO, Hieu T, SHU YUN ZHANG, KUMAR, Rakesh, RUSNAK, David W, TAKLE, Andrew K, WILSON, David M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2006
• Subjects: Alleles; Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Crystallization; Crystallography, X-Ray; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; HT29 Cells; Humans; Imidazoles - chemistry; Imidazoles - therapeutic use; Medical sciences; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Mutation - genetics; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Pharmacology. Drug treatments; Phosphorylation - drug effects; Protein Conformation - drug effects; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - chemistry; Proto-Oncogene Proteins B-raf - genetics; Tumors; Xenograft Model Antitumor Assays; Enzyme; Transferases; Index; Malignant tumor; Gene expression; Carcinogenesis; BRAF Gene; Treatment; Kinase; C-Onc gene; Genetics; Inhibitor; Protooncogene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-2554

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.