This article provides a systematic review of the central role of lysine acetylation in gene regulation and disease, with a focus on the latest advances in lysine acetyltransferases (KATs) and bromodomains (BrDs) as drug targets. It covers their structures, functions, and the current state of small-molecule inhibitor development, offering new directions for the treatment of diseases such as cancer and inflammation.
Literature Overview
The article 'Targeting Lysine Acetylation Readers and Writers,' published in Nature Reviews. Drug Discovery, reviews and summarizes lysine acetylation as a critical post-translational modification of both histone and non-histone proteins, catalyzed by 'writer' enzymes known as lysine acetyltransferases (KATs) and recognized by 'reader' domains such as bromodomains (BrDs). The article systematically introduces the classification and structural features of KATs and BrDs, along with their essential roles in gene expression, chromatin architecture, and epigenetic regulation—particularly their aberrant activation in diseases like cancer. The authors also highlight recent progress in the design of small-molecule inhibitors targeting KATs and BrDs, including strategies for developing selective and dual-target inhibitors, and discuss their potential in preclinical and clinical studies. Additionally, the article explores the role of BET proteins in liquid-liquid phase separation and their emerging mechanisms in transcriptional regulation, broadening the understanding of the biological significance of these targets. Although no KAT or BrD inhibitor has yet received FDA approval, several clinical trials are underway, with promising data from Pelabresib combination therapy in myelofibrosis indicating progress toward clinical translation. The article emphasizes the challenges and opportunities in developing highly selective, low-toxicity epigenetic drugs, offering a comprehensive roadmap for future drug discovery targeting the acetylation pathway.Background Knowledge
Lysine acetylation is a key post-translational protein modification that primarily occurs on the N-terminal tails of histones. By neutralizing the positive charge of lysine residues, it alters chromatin structure and promotes gene transcription. This process is catalyzed by lysine acetyltransferases (KATs) and reversed by lysine deacetylases (KDACs), with 'reader' proteins containing bromodomains (BrDs) recognizing the acetylated marks. KATs include p300/CBP, the MYST family, and PCAF/GCN5, all of which play crucial roles in regulating enhancer activity, DNA repair, cellular metabolism, and immune responses. BrDs are widely present in transcriptional regulators, such as the BET family (BRD2/3/4/BRDT), which recruit transcriptional machinery by binding acetylated histones to drive expression of oncogenes like MYC. Due to their frequent dysregulation in various cancers, targeting KATs and BrDs has become a major focus in epigenetic therapy. While KDAC inhibitors have already been approved for hematological malignancies, small-molecule inhibitors targeting KATs and BrDs remain in clinical development. Current challenges include improving inhibitor selectivity, overcoming drug resistance, understanding functional redundancy, and developing bifunctional or degrader molecules (e.g., PROTACs). Furthermore, the discovery of new mechanisms such as liquid-liquid phase separation has enriched the regulatory network of BrD proteins, suggesting a need for more sophisticated targeting strategies. Therefore, a deeper understanding of the structure and function of KATs and BrDs, along with the development of potent and specific chemical probes, is essential for advancing epigenetic drug discovery into clinical applications.
Research Methods and Experiments
This article employs a review-based approach to systematically integrate recent findings on the 'writing' and 'reading' mechanisms of lysine acetylation. The authors begin by analyzing the catalytic domain features, substrate specificities, and roles in chromatin remodeling of different KAT families (HAT1, PCAF/GCN5, p300/CBP, MYST), based on structural biology data. By comparing the three-dimensional structures of various KATs, they reveal conserved and divergent aspects of acetyl-CoA binding and catalytic mechanisms, providing a theoretical foundation for the design of selective inhibitors. Subsequently, the article details the structural characteristics of bromodomains (BrDs), particularly their hydrophobic pockets and hydrogen-bonding networks that recognize acetylated lysine, and uses NMR and X-ray crystallography data to elucidate functional differences between canonical and non-canonical BrDs. The authors further summarize recent progress in developing small-molecule inhibitors targeting KATs and BrDs, including structure-based drug design, high-throughput screening, and optimization through chemical modification. Special emphasis is placed on the classification of BET inhibitors (Type I–IV), covering pan-BET inhibitors, BD1- or BD2-selective inhibitors, and dual-target inhibitors, with their anti-tumor and anti-inflammatory activities evaluated using in vitro enzymatic assays, cellular functional tests, and animal models. In addition, clinical trial data are included to analyze the safety, pharmacokinetics, and preliminary efficacy of representative compounds.Key Conclusions and Perspectives
Research Significance and Prospects
This article provides a comprehensive summary of recent advances in targeting the 'writing' and 'reading' systems of lysine acetylation, offering a detailed roadmap for epigenetic drug discovery. By deeply analyzing the structure and function of KATs and BrDs, it reveals the structural basis for developing highly selective small-molecule inhibitors, facilitating the transition from non-selective to subtype-specific inhibitors. In particular, the discovery of functional divergence between BD1 and BD2 domains of BET proteins offers new insights for precisely intervening in specific disease pathways. The emergence of dual-target inhibitors represents a novel strategy for multi-target synergistic therapy, potentially overcoming drug resistance and enhancing therapeutic outcomes.
Future research should further explore the role of non-catalytic functions (e.g., liquid-liquid phase separation) in disease and develop degrader molecules (e.g., PROTACs) for more sustained target suppression. Additionally, biomarker studies should be strengthened to identify patient populations sensitive to specific inhibitors. Moreover, the development of tissue-specific delivery systems and exploration of novel chemical scaffolds will help improve pharmacokinetics and safety. Overall, drug development targeting the acetylation pathway is at a critical translational stage, with the potential to deliver breakthrough therapies for cancer, inflammation, and neurodegenerative diseases.
Conclusion
This article systematically elucidates the central role of lysine acetylation in epigenetic regulation, focusing on the structure, function, and therapeutic potential of 'writer' enzymes (KATs) and 'reader' domains (BrDs). The authors provide a detailed review of the biological roles of p300/CBP, MYST family, and BET proteins, emphasizing their critical functions in gene transcription, chromatin remodeling, and disease pathogenesis. The article highlights recent progress in developing small-molecule inhibitors targeting these proteins, including pan-BET inhibitors, BD1/BD2-selective compounds, and dual-target inhibitors, along with their performance in preclinical and clinical studies. Although challenges remain in selectivity and toxicity, novel inhibitor strategies—such as subtype selectivity and dual targeting—offer promising avenues for improved efficacy and safety. This work provides a comprehensive review of epigenetic drug discovery and outlines future directions, including exploring phase separation mechanisms, developing degraders, and optimizing delivery systems, making it a highly valuable reference for the field.
