Proteolysis-targeting chimeras mediate the degradation of bromodomain and extra-terminal domain proteins.

Bromodomain and extra-terminal domain (BET) protein family plays an important role in regulating gene transcription preferentially at super-enhancer regions and has been involved with several types of cancers as a candidate. Up to now, there are 16 pan-BET inhibitors in clinical trials, however, most of them have undesirable off-target and side-effects. The proteolysis-targeting chimeras technology through a heterobifunctional molecule to link the target protein and E3 ubiquitin ligase, causes the target's ubiquitination and subsequent degradation. By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimeras.