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

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 pharma...

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Published in:ACS medicinal chemistry letters 2015-09, Vol.6 (9), p.961-965
Main Authors: Williams, Teresa E, Subramanian, Sharadha, Verhagen, Joelle, McBride, Christopher M, Costales, Abran, Sung, Leonard, Antonios-McCrea, William, McKenna, Maureen, Louie, Alicia K, Ramurthy, Savithri, Levine, Barry, Shafer, Cynthia M, Machajewski, Timothy, Renhowe, Paul A, Appleton, Brent A, Amiri, Payman, Chou, James, Stuart, Darrin, Aardalen, Kimberly, Poon, Daniel
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Language:English
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml500526p