Current landscape of BRD4 inhibitors: Selective targeting and protein degradation for enhanced efficacy

The bromodomain and extra-terminal domain (BET) family of proteins has been implicated as a crucial factor in the pathogenesis of numerous diseases by regulating gene expression and chromatin dynamics through its bromodomains, which bind to acetylated lysine residues. As a key member of the BET protein family, BRD4 has emerged as a potential therapeutic target for a wide spectrum of diseases, including cancer, inflammation, fibrosis, cardiovascular disorders, and viral infections. In recent years, pan-BET inhibitors have advanced in clinical studies, but their efficacy remains limited by toxicity, resistance, and pharmacokinetics. In contrast, BRD4-BD1 and BRD4-BD2 selective inhibitors show strong potential against viral, inflammatory, oncologic, and neurodegenerative diseases, with high efficacy, low toxicity, and favorable pharmacokinetics. Moreover, protein degradation strategies targeting BRD4 offer novel approaches to overcome drug resistance. This work reviews the current status of research on BRD4 inhibitors.