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

ABSTRACT: 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.

SUBMITTER: Williams TE

PROVIDER: S-EPMC4569875 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Williams Teresa E TE Subramanian Sharadha S Verhagen Joelle J McBride Christopher M CM Costales Abran A Sung Leonard L Antonios-McCrea William W McKenna Maureen M Louie Alicia K AK Ramurthy Savithri S Levine Barry B Shafer Cynthia M CM Machajewski Timothy T Renhowe Paul A PA Appleton Brent A BA Amiri Payman P Chou James J Stuart Darrin D Aardalen Kimberly K Poon Daniel D

ACS medicinal chemistry letters 20150803 9

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. ...[more]

PMID: 26396681

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