Epigenetics refers to a broad biological regulatory system that controls gene expression without altering the sequence of the genes themselves. Genes are composed of DNA, and in nature, this DNA is wrapped around a core of proteins known as histones. Together, the DNA and histone proteins form a complex known as chromatin that is the basic structural component of chromosomes.
Gene regulation is dependent on chromatin structure. The dynamics of chromatin structure are regulated through multiple mechanisms by chromatin modifying proteins or CMPs. Some CMPs place chemical groups or “marks” onto specific sites on histones or DNA, some remove these marks in site-specific ways, others recognize the uniquely marked sites on histones and bind to these marked sites, and still other CMPs drive topological changes to histone-DNA interactions within chromatin. Where, when and how such chromatin structural changes occur, determines which genes in a cell are turned “on” or “off” at any particular time. When the function of these CMPs is altered, the program of gene expression is changed to either a transcriptionally expressive or repressive state, which can lead to disease.
Epizyme’s Epigenetic Scientific Platform
We’re focused on identifying and developing the next generation of cancer medicines that target key epigenetic modulators and have spent the last decade developing a proven research platform to systematically identify and target key epigenetic targets that drive tumor cell proliferation and survival.
The use of a proprietary CRISPR screening technology has allowed us to evaluate the role of over 600 epigenetic related targets in more than 400 cancer cell lines. We’ve observed that validated targets tend to cluster within certain epigenetic gene families enabling a broader gene family approach to drug discovery. The individual targets within these families are further credentialed based on their disease-related biology, “druggability,” clinical development path, commercial opportunity, and importantly, the medical need.
This platform has led to a large number of prioritized targets for which we have identified inhibitors through the application of our internal drug discovery engine and our proprietary compound library. This library has been extensively characterized against multiple epigenetic target families using large cross-screens, providing compounds for rapid lead generation, as well as critical information about off-target activities.