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Demonstration of a Genetic Therapeutic Index for Tumors Expressing Oncogenic BRAF by the Kinase Inhibitor SB-590885

Departments of ¹ Oncology, ² Drug Metabolism and Pharmacokinetics, ³ Enzymology and Mechanistic Pharmacology, ⁴ Medicinal Chemistry, MMPD CEDD, GlaxoSmithKline, Collegeville, Pennsylvania; ⁵ Department of Computational, Analytical and Structural Sciences, Discovery Research, GlaxoSmithKline, King of Prussia, Pennsylvania; ⁶ Department of Medicinal Chemistry, NGI CEDD, GlaxoSmithKline, Harlow, Essex, United Kingdom; ⁷ Abramson Family Cancer Research Institute and Abramson Cancer Center at the University of Pennsylvania, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ⁸ Department of Gastroenterology in Shanghai Rui Jin Hospital, Shanghai Second Medical University, Shanghai, China; ⁹ Cambridge Research Institute/Cancer Research UK, Cambridge, United Kingdom; ¹⁰ Exelixis, Inc., South San Francisco, California; and ¹¹ The Wistar Institute, Philadelphia, Pennsylvania

Requests for reprints: Denis R. Patrick, Department of Oncology, GlaxoSmithKline, Collegeville, PA 19426. E-mail: denis.r.patrick{at}gsk.com or David A. Tuveson, Cambridge Research Institute/Cancer Research UK, Cambridge, United Kingdom. E-mail: david.tuveson{at}cancer.org.uk.

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. (Cancer Res 2006; 66(23): 11100-5)

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