Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma

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• 作者：Teresa E. Williams ; Sharadha Subramanian ; Joelle Verhagen ; Christopher M. McBride ; Abran Costales ; Leonard Sung ; William Antonios-McCrea ; Maureen McKenna ; Alicia K. Louie ; Savithri Ramurthy ; Barry Levine ; Cynthia M. Shafer ; Timothy Machajewski ; Paul A. Renhowe ; Brent A. Appleton ; Payman Amiri ; James Chou ; Darrin Stuart ; Kimberly Aardalen ; Daniel Poon
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：961-965
• 全文大小：333K
• ISSN：1948-5875

文摘

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.