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

  • ACS Med Chem Lett. 2013 Feb 7;4(3):358-62. doi: 10.1021/ml4000063.
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
  • 1. Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
  • 2. Computational and Structural Chemistry, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
  • 3. Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States.
  • 4. Platform Technology & Science, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States.
PMID: 24900673 DOI: 10.1021/ml4000063
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.