Recent Advances and Strategies in BET Bromodomain Inhibition for Drug Discovery

BET proteins, which function as epigenetic readers to modulate gene expression and drive cancer progression, have emerged as promising targets for novel epigenetic anticancer therapies. Although preclinical models and initial clinical trials have demonstrated the anticancer potential of BET inhibitors, Pan-BET inhibitors often exhibit unsatisfied tolerability, dose-limiting toxicities, and limited efficacy as monotherapies. Recent studies highlight that selective BET inhibitors targeting individual bromodomains (BET-BD1 or BET-BD2) offer distinct advantages over pan-inhibitors, including reduced toxicity profiles. Notably, certain selective BET inhibitors demonstrate comparable or superior therapeutic efficacy in treating inflammatory diseases and cancers compared to pan-inhibitors. Consequently, the development of domain-selective BET inhibitors has become a focal point in medicinal chemistry research. This review summarizes the structural and functional characteristics of BET proteins, elucidates the differential binding preferences and biological roles of BD1 and BD2 domains, and systematically outlines recent advancements over the past five years in BD1- and BD2-selective BET inhibitors. Furthermore, it provides a detailed overview of dual-target inhibitors and degraders. Finally, perspectives on future research directions for BET-targeted therapeutics are discussed.