BET bromodomain inhibitors

Lysine acetylation creates docking sites for epigenetic reader domains of BET bromodomain proteins that have emerged as principal regulators of linage specific gene transcription. The development of potent and highly selective inhibitors, that have been soon widely available, enabled mechanistic studies in a diversity of disease models leading to a rapid translation into the clinic. Initial studies on pan-BET inhibitors lead now to second generation inhibitors with improved domain selectivity, but also to highly potent bifunctional and dual inhibitors extending the toolbox for basic research on acetylation dependent transcription, BET associated diseases and further translational efforts targeting this interesting family of epigenetic reader domains. Targeting strategies developing BET inhibitors. Shown are examples of a selective bromodomain 1 (BD1) as well as a BD2 and a pan-BET inhibitor and a PROTAC. [Display omitted] •pan-BET inhibitors have entered clinical studies in diverse cancers.•Second generation inhibitors have now been designed for increased domain selectivity.•Bi-functional and dual inhibitors extend the toolbox of available research agents.•New generation of BET inhibitors as promising agents for future clinical studies.