Epigenetics > The Next Big Thing in Biotech?

Epigenetics is the hot word right now in biotech - but why? 

Epigenetics is the study of slight modifications to the genome that result in the turning off or turning on of a gene or a series of genes.  Because epigenetic modifiers can have such profound effects on gene expression (think turning off an oncogene), they make attractive targets.

However, just because epigenetic modifiers are cool targets does not mean they are druggable.  For example, a single histone methyltransferases (adds methyl groups) or histone acetyltransferases (adds acetyl groups) often targets multiple genes and can even have opposing (activating or deactivating) functions depending on the specific gene target.  This makes finding lead compounds that exhibit strong specificity and efficacy incredibly challenging.

The bulk of epigenetic drug development activity to date has been to make DNA more sensitive to chemotherapy.  Most chemotherapy agents function by intercalating and disrupting double-stranded DNA, which is not so easy when DNA is bundled around histones.  New epigenetic drugs like the HDAC inhibitors function to unwind the bound DNA to make it easier for the chemotherapy agents to attack it.  

Beyond the HDAC inhibitors, epigenetics is really in its infancy.  There are a number of interesting university startups in the epigenetic space that I have been following.  

Select University Startups

Acetylon Pharma: Acetylon was formed last year to develop drugs that target HDAC enzymes (histone deacetylases), which are involved in regulating the expression of certain genes in most types of cells. Interfering with these enzymes can interfere with gene expression, making them popular targets among pharma and biotech companies developing drugs to treat cancer and other diseases. The problem with many HDAC inhibitors is that they can disrupt the function of healthy cells, causing side effects such as vomiting, fatigue, and even heart attacks.  The core technology was licensed from Harvard University (Dana-Farber).

Acylin Therapeutics: Acylin is the first biotech company to successfully target the histone acetyltransferase (HAT) designated p300/CBP. HATs are a class of enzymes catalyzing protein acetylation and fundamental to the molecular pathology of cancer, metabolic disease, and neurodegeneration. The company has also licensed technology for inhibiting Ghrelin O-Acyl Transferase (GOAT), an enzyme directly linked to maintenance of energy balance and body composition, including GOAT family inhibitors that substantiate a pharmacologic approach for management of metabolic disorders through ghrelin regulation.  The core technology was licensed from Johns Hopkins and the Wistar Institute.

CellCentric: CellCentric has established a hub & spoke network of scientific excellence across different but overlapping areas of research within epigenetics, including chromatin modifying enzymes, cancer initiation models, pluripotency and embryogenesis.  The Discovery Network comprises over 30 of the key epigenetics Principal Investigators (PIs) and their laboratories, from leading institutions around the world.  Network includes University of Cambridge, Harvard, USC, Wistar, and many others.

Constellation Pharmaceuticals: Constellation is developing a pipeline of preclinical drug candidates with the initial focus of modulating epigenetic function, particularly histone modifications, to discover and develop novel drugs for oncology. Constellation’s technology platform is also applicable to other therapeutic areas including autoimmune, inflammatory and neurological diseases. The core technology was licensed from Harvard University, NYU, and The Rockefeller University.

Epizyme: Epizyme’s proprietary product platform provides a robust foundation for the discovery of small molecule inhibitors of high-value HMT targets in cancer.  KMTs transfer a methyl group onto specific lysine residues of substrate proteins and the RMTs transfer a methyl group onto specific arginine residues of their substrate proteins. Both of these classes of HMTs share in common a universal methyl donating cofactor, S-adenosyl methionine (SAM). The core technology was licensed from MIT, and University of North Carolina.

Syndax Pharma: Entinostat is a novel inhibitor of class I histone deacetylases (HDAC), key enzymes that alter the structure of chromatin to control gene expression. Designed to selectively target the HDAC isoforms most relevant to the biology of tumors, entinostat can specifically reactivate genes in cells where cancers have modified epigenetic control over the patterns operating in normal cells. This aberrant gene expression can result in reversible, epigenetically-based drug tolerance.  The core technology was licensed from The Salk Institute, with additional IP from Duke University.