Pharmacological targeting of GCN5/PCAF (KAT2A/B): current drug discovery strategies and translational potential.

The catalytic activity of general control non-derepressible 5 (GCN5) and p300/CBP-associated factor (PCAF) plays a pivotal role in numerous physiological and pathological conditions, underscoring its potential as a therapeutic target. However, developing clinically viable modulators remains challenging due to highly conserved catalytic domains within the GCN5-related N-acetyltransferases family. Recent advances have shifted the focus from classical catalytic-site inhibitors to noncatalytic-domain inhibitors, improving selectivity and specificity. Emerging approaches, including proteolysis-targeting chimeras, acetylation-targeting chimeras, high-throughput screening and rational drug design, are reshaping the landscape of inhibitor development. This review outlines the structural features, functions and diverse roles of GCN5/PCAF in disease pathology, with an emphasis on inhibitor design strategies. We also propose a framework for inhibitor development that integrates active-site engagement, pharmacophore modelling and function-driven targeting strategies to bridge the gap between early-stage discovery and translational potential.