Recent progress and structural analyses of domain‐selective BET inhibitors

Abstract Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine‐ε‐N‐acetylation (K ac ), bromodomains serve as recognition modules (“readers”) of this activating epigenetic mark and competition of the bromodomain‐K ac interaction with small‐molecule inhibitors is an attractive strategy to control aberrant bromodomain‐mediated gene expression. The bromodomain and extra‐terminal (BET) family proteins contain eight similar bromodomains. These BET bromodomains are among the more commonly studied bromodomain classes with numerous pan‐BET inhibitors showing promising anticancer and anti‐inflammatory efficacy. However, these results have yet to translate into Food and Drug Administration‐approved drugs, in part due to a high degree of on‐target toxicities associated with pan‐BET inhibition. Improved selectivity within the BET‐family has been proposed to alleviate these concerns. In this review, we analyze the reported BET‐domain selective inhibitors from a structural perspective. We highlight three essential characteristics of the reported molecules in generating domain selectivity, binding affinity, and mimicking K ac molecular recognition. In several cases, we provide insight into the design of molecules with improved specificity for individual BET‐bromodomains. This review provides a perspective on the current state of the field as this exciting class of inhibitors continue to be evaluated in the clinic.