Targeting Non-BET Bromodomains: Emerging Opportunities in Drug Discovery

Bromodomains, epigenetic "readers" of acetylated lysine marks, represent promising therapeutic targets. The clinical limitations of BET inhibitors, together with growing insights into the distinct functions of non-BET members (e.g., ATAD2, CBP/p300, and BRD7/9), highlight the importance of pursuing their pharmacological potential. This Perspective examines recent medicinal chemistry advances in the development of non-BET bromodomain inhibitors, focusing on structure-guided strategies to address selectivity challenges within conserved KAc-binding pockets. Key topics include: (1) the structural and functional diversity of non-BET bromodomains in oncology, inflammation, and metabolic diseases; (2) innovative design strategies, such as allosteric covalent modulation and the development of PROTACs and other heterobifunctional molecules; and (3) preclinical/clinical progress of leads targeting CBP/p300, BRD7/9, and SMARCA2/4. Pharmacokinetic challenges (e.g., blood-brain barrier penetration, tissue-specific delivery) and opportunities in AI-driven discovery and nonepigenetic synergies are evaluated. By integrating mechanistic insights with medicinal chemistry breakthroughs, this Perspective aims to inform the rational development of selective non-BET bromodomain modulators with enhanced therapeutic potential.