Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors.

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.

• Authors: Tara R Rheault, John C Stellwagen, George M Adjabeng, Keith R Hornberger, Kimberly G Petrov, Alex G Waterson, Scott H Dickerson, Robert A Mook Jr, Sylvie G Laquerre, Alastair J King, Olivia W Rossanese, Marc R Arnone, Kimberly N Smitheman, Laurie S Kane-Carson, Chao Han, Ganesh S Moorthy, Katherine G Moss, David E Uehling
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 4 Issue 3 Pg. 358-62 (Mar 14 2013) ISSN: 1948-5875 [Print] United States
• PMID: 24900673 (Publication Type: Journal Article)