Advances in selective inhibitors targeting the BD1 and BD2 domains of BET proteins.
The bromodomain and extra-terminal (BET) protein family are key epigenetic regulators. Their aberrant expression causes widespread gene dysregulation, which disrupts normal cellular functions and is strongly implicated in diverse human pathologies, including inflammation, cancer, cardiovascular diseases, and central nervous system disorders. Currently, several BET inhibitors have entered clinical trials. However, most are pan-BET inhibitors, whose lack of selectivity is associated with adverse effects such as dose-limiting toxicities and thrombocytopenia. Therefore, the development of highly selective inhibitors targeting individual bromodomains (BD1 or BD2) within the BET family has become a key focus in the field. This review outlines the structure and function of BET proteins and summarizes recent advances in the discovery of domain-selective BET inhibitors. It aims to deepen the mechanistic understanding of BET proteins and lay the groundwork for the rational design of next-generation, high-selectivity therapeutics.