About Epigenetics

Instructions for the genetic code

There are approximately 20,000 protein coding genes that produce the building blocks for the human body to function. In order to know where and when to act, genes need instructions. Epigenetic regulatory elements provide these instructions.

Each human cell packs nearly two meters’ worth of DNA molecules. These DNA molecules are wound, like thread around a spool, on protein complexes containing histones. DNA and the histones together comprise chromatin.

Unwound, opened chromatin allows cells to transcribe and use the genetic information coded by DNA. Compacted and closed chromatin turns off transcription and allows DNA to be silenced or protected. Chemical modifications by epigenetic regulatory factors drive changes in chromatin structure, and these changes help control gene expression by turning off (silencing) or turning on (activating) genes at the right times and in the appropriate locations in the body. Improper gene activation or silencing by loss of epigenetic control can lead to erroneous gene expression that may contribute to the development of diseases ranging from cancer and autoimmune disorders to diabetes and neurological conditions.

Over the past 20 years, researchers identified many of the enzymes and proteins responsible for regulating chromatin structure and function. Several hundred enzymes add and remove chemical modifications on chromatin. Several hundred more proteins physically bind to chromatin through interaction with these chemical modifications. These enzymes and binding proteins comprise the cell “instruction manual” for gene regulation by opening and closing chromatin or modifying its structure to help control when and where genes are expressed.

Harnessing epigenetics to treat disease

Extensive research has shown that diseased cells, such as tumors, can usurp epigenetic control events, leading to abnormal gene expression, which is critical to the development and progression of the underlying disease. Inhibiting epigenetic control proteins with small-molecules and restoring normal gene expression can enable development of important new treatments that have the potential to address significant medical needs.

 

Our Approach

Constellation Pharmaceuticals is leading the way in creating therapies that target multiple classes of epigenetic regulators to treat disease. Broadly, these regulators fall into three groups—writers (chemically modify chromatin), readers (protein binders to chemical modifications), and erasers (remove chemical modifications). Each of these protein classes provide a rich collection of therapeutic targets.

Illustration of how various chromatin regulatory mechanisms (multiple classes of reader, writer and eraser proteins) impact chromatin structure to alter access to DNA

The company has developed unique capabilities to understand the biological context in which these regulators operate, develop small-molecule drugs that modulate their activity, and apply differentiated clinical development programs built on translational insights. The research team has produced five small-molecule development candidates against all three major chromatin regulatory classes. Further, the company has shared its work in approximately 35 peer-reviewed papers.

Modulation of chromatin regulatory pathways by small molecules that target chromatin writer, reader and eraser proteins alter transcriptional programs that cancer cells depend on.
Constellation’s fully integrated drug discovery and development platform is creating a robust pipeline of programs across the writer, eraser, and reader classes of epigenetic targets to develop new drugs in oncology.

Following the science

Our research exploits inhibition of chromatin regulatory pathways as a means to selectively control gene expression in cancer cells and in the tumor or immune microenvironment. Strategies for utilizing epigenetic targets to develop new therapies for patients have evolved over the last decade. Early approaches to targeting epigenetic gene regulation—such as DNA methyltransferase and histone deacetylase (HDAC) inhibitors—resulted in expression changes across thousands of genes which led to unintended effects. Importantly, interest in epigenetics arose at a time when the clinical limitations of the earlier generation of targeted therapies, such as kinase inhibitors, became more clear. The genetically-targeted development hypotheses for kinase inhibitors became the rulebook by which investigators pursued initial development of therapies based on inhibition of epigenetic regulatory systems. Early development programs, including our programs, focused on driver mutations that resulted in over-expression of key epigenetic regulatory proteins like EZH2.

Applying translational insights

Cancers occur in people, in part, due to changes in genes that control signaling pathways governing cell differentiation and function. Epigenetic dysregulation of these pathways will render cancer cells dependent on an abnormal gene expression pattern that includes activation of pro-tumor genes or silencing of tumor suppressor genes. Furthermore, research has shown that epigenetic regulators are being utilized by cancer cells to activate resistance mechanisms against current treatment options, rendering them less effective initially, or over time. The company’s translational medicine researchers aim to link these dysregulated pathways to defined patient populations that are most likely to respond to our treatments. In our preclinical research, we develop patient enrichment hypotheses and will seek diagnostic assays that help us test these hypotheses in enriched clinical studies.

Looking ahead

New therapies based on small-molecule inhibition of key epigenetic targets have the potential to impact patient care in two major ways over time. In the near-term, epigenetic regulatory systems have been shown to be associated with tumors that have developed resistance to chemotherapy, targeted therapy, and immunotherapy. Inhibition of individual chromatin regulators may directly induce cancer cell death or result in transcriptional reprogramming (“epigenetic priming”) that allows clinicians to overcome primary and acquired resistance to existing cancer therapies. We have implemented clinical development approaches for our most advanced pipeline programs that use this insight to enable combination therapy approaches that can restore response to foundational therapies in key tumor types. Over the longer-term, improved understanding of transcriptional regulation network biology, as well as different small-molecule approaches to targeting epigenetic regulators, should also enable first-line use in tumor types or contexts not accessible with current treatment options.

 

Therapeutic Applications of Epigenetics

Cancers often occur in people due, in part, to mutations in genes that control signaling pathways governing cell differentiation and function. Dysregulation of these pathways will render cancer cells dependent on an abnormal gene expression that includes activation of pro-tumor genes or deactivation of tumor suppressor genes. Furthermore, research has shown that chromatin regulators are being utilized by cancer cells to activate resistance mechanisms against current treatment options, rendering them less effective initially, or over time.

Overcoming resistance

These insights strongly support the concept of utilizing chromatin regulation as a direct tumor-targeting therapeutic strategy. Inhibition of individual chromatin regulators may directly induce cancer cell death or result in transcriptional reprogramming (“epigenetic priming”) that allows clinicians to overcome primary and acquired resistance to existing cancer therapies.

Our approach identifies cancer cell contexts that are completely dependent on the function of individual chromatin regulatory protein classes.

Applications in immuno-oncology

Abnormal epigenetic regulatory cues promote activation of pro-tumor and silence tumor suppressor functions in cancer cells. Additionally, dysregulation of chromatin regulatory pathways in the tumor microenvironment can promote evasion from immunosurveillance (the body’s ability to recognize abnormal tissue and cells and clear them from the body naturally). Chromatin regulatory proteins are involved in all the processes that contribute to the establishment of an immune-suppressive tumor microenvironment. Inhibition of individual chromatin regulators may inactivate immune-suppressive mechanisms, activate T-cell responses, promote cytokine production and effector immune cell trafficking, and increase the immunogenicity of tumor cells.

Our approach identifies key epigenetic regulatory dependencies in immune cells. For instance, the company has identified molecular mechanisms that render immunosuppressive regulatory T cells dependent on the catalytic activity of the EZH2 methyltransferase. In addition, the company’s platform is aimed at identifying additional epigenetic targets that are responsible for driving resistance to existing immunotherapies. Specifically, the company is targeting the epigenetic mechanisms that “re-wire” immune cells, such as myeloid cells to switch from being immune-suppressive to pro-inflammatory.