Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors
Tara Rheault(Research Triangle Park Foundation), John Stellwagen(GlaxoSmithKline (United States)), George M. Adjabeng(GlaxoSmithKline (United States)), Keith R. Hornberger(Research Triangle Park Foundation), Kimberly G. Petrov(Research Triangle Park Foundation), Alex G. Waterson(Research Triangle Park Foundation), Scott H. Dickerson(GlaxoSmithKline (United States)), Robert A. Mook(GlaxoSmithKline (United States)), Sylvie Laquerre(GlaxoSmithKline (United States)), Alastair J. King(GlaxoSmithKline (United States)), Olivia W. Rossanese(GlaxoSmithKline (United States)), Marc R. Arnone(GlaxoSmithKline (United States)), Kimberly N. Smitheman(GlaxoSmithKline (United States)), Laurie S. Kane-Carson(Research Triangle Park Foundation), Chao Han(GlaxoSmithKline (United States)), Ganesh S. Moorthy(GlaxoSmithKline (United States)), Katherine G. Moss(GlaxoSmithKline (United States)), David Uehling(GlaxoSmithKline (United States))
Cited by 256Open Access
Abstract
Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
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