Epigenetics in Drug Discovery: Modulating Gene Expression for Health

Epigenetics unraveled
Epigenetics in health and disease
Epigenetics in drug discovery
Case studies and success stories
Challenges and ethical considerations
The future of epigenetics in medicine
Further reading

Epigenetics is an emerging field of scientific research exploring the study of gene expression changes that occur without alterations to the DNA sequence itself.

Image Credit: Juan Gaertner/Shutterstock.com

Processes like DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling often drive these changes. Environmental factors can influence epigenetic modifications and play a crucial role in gene regulation, development, and disease susceptibility, offering insights into personalized medicine and potential therapeutic strategies.

Understanding epigenetics gives healthcare professionals and researchers insights into the molecular processes that influence health and diseases, potentially leading to better disease prevention, early detection, and more targeted treatments.

Epigenetics unraveled

Epigenetics focuses on modifications to the structure and function of DNA and the associated proteins that influence how genes are switched on and off and their activity levels without changing the genetic code itself.

Gene regulation is fundamental to development, tissue specificity, responses to environmental stimuli, and disease processes. Epigenetics plays a significant role in controlling and fine-tuning gene expression, using DNA methylation and histone modifications to determine whether genes are active or silenced.

DNA methylation is a process whereby a methyl group is added to specific sites on a molecule of DNA, a modification that typically represses gene expression by preventing the binding of active proteins, influencing which genes are turned on or off.

Histone modification is the addition or removal of chemical groups, such as acetyl or methyl groups, to histone proteins. Histone proteins play a role in the packaging of DNA into chromatin.

Both DNA methylation and histone modifications regulate gene activity, respond to environmental factors, influence disease susceptibility, impact aging, and can even be inherited across generations, influencing gene expression and health.

Epigenetics in health and disease

Epigenetics plays a pivotal role in various health conditions and diseases, including cancer and neurological disorders.

In cancer, epigenetic patterns such as DNA methylation and histone modifications are known to silence tumor suppressor genes or activate oncogenes, leading to uncontrolled cell proliferation.

Novel epigenetic therapies such as DNA methyltransferase inhibitors and histone deacetylase inhibitors aim at reversing these changes and halting cancer growth.

Neurological disorders such as Alzheimer's, Parkinson's and schizophrenia are influenced by epigenetic modifications that that impact gene expression linked to neurodegeneration and synaptic plasticity.

Epigenetics in drug discovery

Researchers have found that differences in the epigenetic states between healthy and diseased tissues can serve as valuable biomarkers for disease.

Epigenetics has significantly impacted drug discovery, with several drugs and therapies targeting epigenetic modifications now available. Despite only a limited number of approved drugs in this category, researchers are exploring innovative approaches, such as protein degraders (PROTACs) and antibody-drug conjugates, to enhance the effectiveness and reduce the side effects of epigenetic inhibitors.

Paul Brennan: Chemistry epigenetics and drugs

Strategies involving CRISPR/Cas9 and multitarget assemblage construction are being considered to correct genetic mutations and provide enhanced anticancer effects. The future of epigenetic drug discovery appears promising, with the potential for new agents to enter clinical trials and further therapeutic growth.

Case studies and success stories

Nucleoside-like compounds, the earliest type of methylation inhibitors, have found applications in cancer treatment. One such compound is 5-Azacytidine, known by its market name Vidaza, which was discovered to exhibit cytotoxic effects on cancer cells back in 1968, although its mechanism of action was only more recently unraveled.

This drug is a cytidine analog, where a nitrogen atom replaces Carbon 5. Once inside a cell, it undergoes phosphorylation and becomes part of DNA during replication. DNMT1 recognizes the analog and initiates the usual methyl group transfer. However, the nitrogen substitution in the fifth position results in an irreversible linkage between DNMT1 and aza, leading to enzyme degradation and extensive methylation reductions.

This integration during DNA replication makes it particularly effective against rapidly dividing cancer cells. While it's FDA-approved, there's room for improvement as it's relatively unstable, may have toxic side effects, and isn't available in oral form.

RG108 is a novel small molecule compound designed to inhibit DNA methylation. Unlike other drugs, it doesn't integrate into the target DNA or interact with the DNMT1 gene. Instead, it directly binds to and hampers the activity of the DNMT1 enzyme, which is responsible for DNA methylation.

When tested in the lab using human cancer cell lines, RG108 demonstrated the ability to reverse DNA methylation and reactivate the p16 tumor suppressor gene, thereby slowing down the growth of cancer cells. What makes RG108 particularly promising is its unique mechanism of action, which reduces its toxicity compared to other drugs. It also has the advantage of leaving certain DNA regions unaffected, enhancing the stability of hypomethylated chromatin.

These features make RG108 a potentially effective anticancer drug for the future.

Challenges and ethical considerations

Despite its promise, epigenetic drug discovery presents several challenges and ethical dilemmas. One concern is the potential for off-target effects, where drugs may affect genes or processes not originally intended.

The long-term effects of epigenetic drug use are currently unknown. It is possible that these drugs could induce lasting changes in gene regulation, raising questions about their safety and the possibility of health implications later on.

Equitable access to epigenetic therapies is another challenge. As treatments are developed and commercialized, it poses questions about accessibility and affordability. The potential high cost of these innovative therapies may limit the reach of disadvantaged or marginalized groups of people.

The future of epigenetics in medicine

The future of epigenetic research and drug discovery is promising, with a strong focus on tailored treatments and personalized medicine.

This approach utilizes an individual's unique epigenetic profile, meaning medical strategies can be fine-tuned to deliver more effective treatments with fewer side effects. Epigenetics also paves the way for targeted therapies, offering insights into fighting conditions like cancer, neurological disorders, and autoimmune diseases. However, addressing ethical issues, ensuring fair access, and protecting patient privacy is essential.


  • Nepali, K. and Liou, J.-P. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. (2021) Journal of Biomedical Science, 28(1). doi: 10.1186/s12929-021-00721-x.
  • Zhang L, Lu Q, Chang C. Epigenetics in Health and Disease. Adv Exp Med Biol. 2020;1253:3-55. doi: 10.1007/978-981-15-3449-2_1. PMID: 32445090.
  • Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S. Use of epigenetic drugs in disease: an overview. Genet Epigenet. 2014 May 27;6:9-19. doi: 10.4137/GEG.S12270. PMID: 25512710; PMCID: PMC4251063.

Further Reading

  • All Drug Discovery Content
  • Hit to Lead (H2L) Process in Drug Discovery
  • Understanding Lead Optimization
  • Hot Melt Extrusion in the Pharmaceutical and Food Industries
  • Importance of Solubility and Lipophilicity in Drug Development


Last Updated: Nov 1, 2023

Written by

Jenna Philpott

Jenna graduated from Nottingham Trent University in 2022 with a BSc in Biochemistry. She achieved a first in her undergraduate research project which concerned the role of metabolic stress on pancreatic beta cell function, investigating its contribution to the development of type 2-diabetes mellitus (T2DM). The study highlighted the importance of understanding molecular pathways in beta cells for developing prevention measures and new therapeutic options for T2DM. 

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