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Background <p>Epigenetic regulation controls gene expression through reversible chromatin modifications, including DNA methylation, histone acetylation, methylation, phosphorylation, and ubiquitination. Dysregulation of these processes contributes to oncogenesis, neurodegeneration, and metabolic disorders. Small-molecule modulators of chromatin-modifying enzymes are emerging as powerful tools for understanding epigenetic mechanisms and developing targeted therapies.</p> Objective <p>This review aims to synthesize advances in chemical epigenetics by bridging medicinal chemistry, chemical biology, and translational medicine. It highlights the therapeutic relevance of small-molecule modulators, evaluates their clinical progress, and identifies future opportunities in precision medicine.</p> Methods <p>A narrative review approach was employed, integrating evidence from preclinical studies, clinical trials, and technological innovations. The analysis covers rational drug design strategies, such as orthosteric and allosteric inhibitors, proteolysis targeting chimeras (PROTAC)-mediated protein degradation, and dual-targeting approaches, alongside enabling technologies including chemoproteomics, activity-based probes, and CRISPR–dCas9 fusion systems.</p> Results <p>Epigenetic modulators have demonstrated clinical utility in oncology and show promise in neurology, immunology, and cardiometabolism. FDA-approved inhibitors such as vorinostat, azacytidine, and tazemetostat exemplify the therapeutic potential of targeting chromatin regulators. However, challenges persist, including context-specific effects, toxicity, and resistance. Strategies combining multi-omics profiling, and combinatorial therapies are reshaping the clinical trajectory of epigenetic drugs. Emerging frontiers include epitranscriptomics, artificial intelligence-assisted drug discovery, synthetic epigenetic circuits, and exploration of noncanonical functions of chromatin regulators.</p> Conclusion <p>Chemical epigenetics represents both a mechanistic toolkit and a therapeutic framework for precision medicine. Advances beyond traditional methods of the chromatin-based interventions can transform the disease treatment regimen and enable the creation of more specific therapeutic approaches.</p>

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Chemical Epigenetics: Small Molecules Targeting Chromatin Modifiers in Disease Modulation

  • 期刊论文

  • 发表日期：

    2026年3月19日

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  • Benedict Nnachi Alum,
  • Darlington Arinze Echegu,
  • Esther Ugo Alum

摘要

Background

Epigenetic regulation controls gene expression through reversible chromatin modifications, including DNA methylation, histone acetylation, methylation, phosphorylation, and ubiquitination. Dysregulation of these processes contributes to oncogenesis, neurodegeneration, and metabolic disorders. Small-molecule modulators of chromatin-modifying enzymes are emerging as powerful tools for understanding epigenetic mechanisms and developing targeted therapies.

Objective

This review aims to synthesize advances in chemical epigenetics by bridging medicinal chemistry, chemical biology, and translational medicine. It highlights the therapeutic relevance of small-molecule modulators, evaluates their clinical progress, and identifies future opportunities in precision medicine.

Methods

A narrative review approach was employed, integrating evidence from preclinical studies, clinical trials, and technological innovations. The analysis covers rational drug design strategies, such as orthosteric and allosteric inhibitors, proteolysis targeting chimeras (PROTAC)-mediated protein degradation, and dual-targeting approaches, alongside enabling technologies including chemoproteomics, activity-based probes, and CRISPR–dCas9 fusion systems.

Results

Epigenetic modulators have demonstrated clinical utility in oncology and show promise in neurology, immunology, and cardiometabolism. FDA-approved inhibitors such as vorinostat, azacytidine, and tazemetostat exemplify the therapeutic potential of targeting chromatin regulators. However, challenges persist, including context-specific effects, toxicity, and resistance. Strategies combining multi-omics profiling, and combinatorial therapies are reshaping the clinical trajectory of epigenetic drugs. Emerging frontiers include epitranscriptomics, artificial intelligence-assisted drug discovery, synthetic epigenetic circuits, and exploration of noncanonical functions of chromatin regulators.

Conclusion

Chemical epigenetics represents both a mechanistic toolkit and a therapeutic framework for precision medicine. Advances beyond traditional methods of the chromatin-based interventions can transform the disease treatment regimen and enable the creation of more specific therapeutic approaches.