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

  • ACS Med Chem Lett. 2015 Aug 3;6(9):961-5. doi: 10.1021/ml500526p.
Teresa E Williams  1 ,  Sharadha Subramanian  1 ,  Joelle Verhagen  1 ,  Christopher M McBride  1 ,  Abran Costales  1 ,  Leonard Sung  1 ,  William Antonios-McCrea  1 ,  Maureen McKenna  1 ,  Alicia K Louie  1 ,  Savithri Ramurthy  1 ,  Barry Levine  1 ,  Cynthia M Shafer  1 ,  Timothy Machajewski  1 ,  Paul A Renhowe  1 ,  Brent A Appleton  1 ,  Payman Amiri  1 ,  James Chou  1 ,  Darrin Stuart  1 ,  Kimberly Aardalen  1 ,  Daniel Poon  1
Affiliations
  • 1. Global Discovery Chemistry, Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.
PMID: 26396681 DOI: 10.1021/ml500526p
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.

Keywords
B-RAF; MAP; VEGF; serine/threonine kinases; tyrosine kinases.