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

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

来源：ACS Medicinal Chemistry Letters, 2013, 4(3): 358-362.

DOI：10.1021/ml4000063

• B-Raf
• GSK2118436
• dabrafenib
• melanoma
• MAP kinase

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.

• 出版日期2013-3