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. 2013 Feb 7;4(3):358-62.
doi: 10.1021/ml4000063. eCollection 2013 Mar 14.

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

Tara R Rheault  1 , John C Stellwagen  1 , George M Adjabeng  1 , Keith R Hornberger  1 , Kimberly G Petrov  1 , Alex G Waterson  1 , Scott H Dickerson  2 , Robert A Mook Jr  1 , Sylvie G Laquerre  3 , Alastair J King  3 , Olivia W Rossanese  3 , Marc R Arnone  3 , Kimberly N Smitheman  3 , Laurie S Kane-Carson  4 , Chao Han  3 , Ganesh S Moorthy  3 , Katherine G Moss  3 , David E Uehling  1
Affiliations

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

Tara R Rheault et al. ACS Med Chem Lett. .

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.

Keywords: B-Raf; GSK2118436; MAP kinase; dabrafenib; melanoma.

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Figures

Figure 1
Figure 1
Dabrafenib (GSK2118436).
Figure 2
Figure 2
Metabolite identification of 9 in dog hepatocytes.
Figure 3
Figure 3
In vivo efficacy of GSK2118436 in CD1 nu/nu mice bearing A375P F11 (B-RafV600E) tumors (n = 8 per group).
Figure 4
Figure 4
In vivo pharmacodynamic response of a single dose of GSK2118436 in CD1 nu/nu mice bearing A375P F11 (B-RafV600E) tumors (n = 4 per group).
See this image and copyright information in PMC

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