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

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• 作者：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
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：4
• 期：3
• 页码：358-362
• 全文大小：287K
• 年卷期：v.4,no.3(March 14, 2013)
• ISSN：1948-5875

文摘

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; dabrafenib; melanoma; MAP kinase