Advancements in epigenetics opens new doors for drug development

Epigenetic modulation represents a new frontier of pharmaceutical research that is attracting significant attention owing to the potential to differentially regulate gene expression for therapeutic benefit. Within this area there exist several novel target classes that through pharmacological manipulation could build upon the success of the histone deacetylases (HDAC) inhibitors in oncology and extend therapeutic benefits to a broad range of therapeutic indications.

Although the promise of this area is substantial, at present our scientific understanding is immature and there is an urgent need to create tools and technologies that can improve our appreciation of the underlying biology. As both academia and industry efforts expand our knowledge of epigenetic mechanisms, we are likely to observe a significantly increased role for epigenetic perturbation in both the cause and treatment of human disease.

Recent reports, three of which are highlighted in this newsletter, have emphasized the potential utility of developing new drugs against epigenetic targets as well as some of the key early successes in this area. In the review article by Owen and Trzupek [1], multiple examples are given of compounds able to inhibit epigenetic proteins. Of particular interest is the development of compounds that can interfere with the protein–protein interactions of so-called epigenetic ‘readers’.  Designing compounds that interrupt protein–protein interactions while maintaining high specificity has been notoriously difficult so the disclosure of the BRD2, 3, and 4 inhibitor, GSK-762, was a noteworthy accomplishment. The description of a druggable pocket within bromodomain-containing proteins opens up the potential to target a much larger collection of epigenetic proteins that fall outside the tradition enzymatic drug targets. And with this expansion in targets come an expansion in the kinds of diseases that might be addressed and the precision with which gene expression might be modulated.

One of the key lessons learned from the identification of the first reader inhibitors was the power of phenotyptic screens. In Gerard Drewes’ review [2], he notes that most epigenetic proteins exist in large complexes with other proteins. Utilizing isolated proteins, when that is technically feasible, or individual protein domains might not properly recapitulate the in vivo confirmation of these proteins thus producing spurious screening hits and compounds that will be inactive when tested in a cellular context. Deployment of chemoproteomic tools against cell lysates allows for lead molecule identification in a more physiologically relevant background. These same techniques and methods have the additional value of supporting target identification after the conclusion of a phenotypic screen.

Epigenetics drug development has matured to the point that is has delivered multiple compounds to the market, although as Green and Gozani point out [3], all of those drugs are directed for the treatment of cancer. Additionally, epigenetic modifying compounds have characteristically been associated with toxicity issues, necessitating their segregation to oncology indications. So the question remains, is there a place for epigenetic-targeting compounds outside of cancer? Green and Gozani specifically note autoimmune diseases as one area of potential expansion providing the example of I-BET which has been shown to robustly suppress inflammation. The authors also point to rare diseases, like Rett syndrome, as a possible home for epigenetic drugs. This is an area of significant unmet need as less than 5% of rare diseases have an approved treatment and many of them are fatal at an early age. In fact, HDAC inhibitors are currently in clinical trials for at least six different rare diseases including Sickle Cell Disease, Spinal Muscular Atrophy, and Amyotrophic Lateral Sclerosis.
Epigenetics represents an exciting and promising new area of drug discovery. The full set of benefits and limitations inherent in altering these pathways is not well appreciated but with academic/industry partnerships like the Structural Genomics Consortium regularly producing new chemical probes to attack these mechanisms, a vision of the future impact of epigenetics on medicine will soon become much clearer.
Mathew Pletcher is a Director in the Rare Disease Research Unit at Pfizer, Inc. and leads the group’s efforts in Transcriptional Modulation. He received a B.S. in biology from Duquesne University and a Ph.D. in human genetics from the Johns Hopkins School of Medicine. After completing a post-doctoral fellowship at the Genomics Institute of the Novartis Research Foundation, he accepted a position at the Scripps Research Institute as an Assistant Professor in the Molecular Therapeutics Department and the Director of the Genetics and Genomics Core Facility. Mathew next joined Pfizer Global Research and Development, where he founded the Non-clinical Pharmacogenomics laboratory and later played an essential role in the creation of the Compound Safety Prediction Department, serving as the head of its Mechanistic Toxicology laboratory.  
Kevin Lee is CSO and Head of the Rare Disease Research Unit at Pfizer, Inc. Prior to joining Pfizer, Kevin conceptualized and led epigenetics research at GSK and was responsible for the creation of the EpiNova DPU as well as leading the formation of multiple strategic commercial and academic partnerships for the company. Kevin studied pharmaceutical sciences at Nottingham University followed by a PhD in pharmacology at Cambridge. He undertook postdoctoral training as a Wellcome Trust International Prize Fellow before joining the Parke Davis Research unit in Cambridge.
Prior to joining GSK, Kevin lectured at Warwick Medical School, founded Cambridge Biotechnology (acquired by Biovitrum) and Neurosolutions (now Neurodiscovery). Kevin is an author on over 100 peer-reviewed scientific publications, has an MBA from Warwick Business School and has been awarded an honorary Chair in Molecular Pharmacology from the University of Warwick
1.             Owen, D.R. and Trzupek, J.D. (2012) Epigenetic drugs that do not target enzyme activity. Drug Discov. Today: Technologies (0).
2.             Drewes, G. (2012) Future strategies in epigenetic drug discovery. Drug Discov. Today: Ther. Strateg. E121–E127
3.             Green, E.M. and Gozani, O. (2012) Everybody's welcome: The big tent approach to epigenetic drug discovery. Drug Discov. Today Ther. Strateg. 9 E75–E81

Share this article

More services


This article is featured in:
The View From Here


Comment on this article

You must be registered and logged in to leave a comment about this article.