Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.

Abstract

Bromodomain-containing proteins serve as epigenetic regulators, where bromodomains recognize acetylated proteins and histones to drive changes in gene expression. Due to their regulatory role in gene expression, bromodomain-containing proteins have served as important targets for drug-discovery efforts, in particular the bromodomain and extra-terminal (BET) family proteins. The selective targeting of these proteins through both inhibition and targeted protein degradation has revealed diverse biological mechanisms. For BET bromodomain-containing proteins, we discuss the unique biological effects of selective inhibition and degradation for efficacy and clinical safety concerns for both BET inhibitors that have entered Phase III clinical trials and recent BET degrader clinical candidates. We also describe the current inhibitory and targeted protein degradation approaches of non-BET bromodomain-containing proteins. This review summarizes current approaches of bromodomain-targeting inhibition and degradation to provide insight on molecular mechanisms and updates the clinical progress of these modalities as the field awaits the approval of the first bromodomain-targeted therapeutic.