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

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

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.

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