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Drug Discovery: Targeting the Epigenome

Targeting the proteins that make disease-specific epigenetic modifications, such as histone deacetylases, is a new area of drug discovery

The health and behavior of each one of our cells is influenced by both genetics and epigenetics. Drug discovery has historically targeted proteins that are part of a disease-related signaling pathway. However, a new niche is opening up in drug discovery. Pharmaceutical companies have begun to target the proteins that control the genome. As it turns out, epigenetics are druggable targets.1

In general, every cell in the body shares the same DNA,however how that DNA is expressed changes through time and across cell types due to epigenetic regulation. Differences in histone modification, and the consequential accessibility of DNA, contribute both to normal physiological function and to disease. Because histone modifications are disease specific, the proteins that make epigenetic modifications are potential targets for drug discovery. These include histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins, and proteins that bind to methylated histones.2

Acetylation and methylation are the most common epigenetic modifications and, hence, are the most widely studied. Anti-cancer drugs have already been approved that target histone deacetylases: vorinostat and romidepsin.1 Histone methyltransferases, EZH2 and DOT1 have been shown to be druggable targets in laboratory studies, too. These examples provide proof of principle that focusing drug development on epigenetic regulators should yield more leads for the pharmaceutical industry.

One stumbling block in the field is that the academics, who do the front line research that leads to drug discovery at pharmaceutical companies, don’t have access to the tools they need to validate targets and conduct translational research. To address this problem, the Structural Genomics Consortium (SGC) has created an open access database of epigenetic chemical probes to make the necessary reagents more widely available..3 The field of epigenetics is big enough that one company cannot tackle the whole field; an open access approach will benefit all, and should accelerate the drug discovery process.

  1. S. Burridge. Target watch: drugging the epigenome. Nature Reviews Drug Discovery 12, 92-93 (February 2013). doi:10.1038/nrd3943
  2. C.H. Arrowsmith et al. Epigenetic protein families: a new frontier for drug discovery. Nature Reviews Drug Discovery 11, 384-400 (May 2012). doi:10.1038/nrd3674
  3. Why do we need high quality open access chemical probes? SGC website.