●  A new science

●  A new platform

●  Epigenetics discoveries

●  Glossary

Epigenetics:  A new platform for drug discovery

Epigenetics is a revolutionary new platform of discovery that offers possibility and promise, truly above and beyond the genome.

Epigenetic regulators, through interactions with the genome -- modulate the structure, function and accessibility of the genome, thereby impacting gene expression and, ultimately, determining the production or non-production of proteins. The mis-regulation of genes by epigenetic regulators are the source of many diseases and disorders.

Hundreds of epigenetic regulators have recently been identified, many of which are chromatin-binding or chromatin-modifying enzymes, such as histone lysine methyltransferases and demethylases. An increasing number of these enzymes have been associated with neurodegenerative disorders, metabolic diseases, inflammation, and most notably, cancer.

Drugs directed against this emerging class of gene-regulating enzymes promise entirely novel approaches to the treatment of human disease through preventing the series of chain reactions that are initiated when the enzymes first interact with the chromatin.

Constellation is developing a deep 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.

Cancer: Epigenetics Proven to Play Critical Role

Constellation’s initial therapeutic focus will be in cancer, as it is known that many cancers are caused by epigenetic regulation gone awry. For example deacetylation of histone proteins causes the DNA to wrap more tightly around the histones, interfering with the transcription of genes by blocking access to them, resulting in the reduction in gene expression. If the genes affected are tumor suppressor genes – whose function is solely designed to suppress erroneous cell growth -- cancer can result.

These observations have prompted the development of non-selective therapeutic agents, such as histone deacetylases (HDAC) inhibitors. However, to date, these drugs have demonstrated limited efficacy in clinical trials, possibly due to their targeting of a broadly acting group of enzymes, rather than highly specific ones.

There are new insights into a growing number of histone modifying epigenetic enzymes which have been identified as translocated, amplified or overexpressed in a variety of tumors. Blocking the activity of these gene-regulating enzymes represents a potentially new and powerful strategy to treat cancer.