Despite recent advances in cancer treatment, significant unmet need persists.  Small molecule approaches remain attractive methods to address many oncologic targets, including the bromodomain and extra-terminal (BET) proteins.  We previously disclosed a carboline-containing clinical candidate (BMS-986158) that demonstrated BET-mediated tumor inhibition in preclinical models.  Herein, we describe efforts towards a second-generation inhibitor.  Deuteration and fluorination strategies were pursued to reduce clearance.  Concurrent with these studies, heterocyclic phenyl replacements were employed to drive increases in free fraction and aqueous solubility.  This work culminated in the identification of potent BET inhibitors with increased exposure across preclinical species and robust efficacy in a mouse solid-tumor model.

Discovery of potent BET inhibitors as potential treatments for cancer

256th National Meeting (2018)

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