Selecting Appropriate Targets

In selecting appropriate targets for drug discovery, several criteria must be considered. Chief among these are target validation, target tractability and unmet patient need.

Target Validation
Target validation is a nebulous term, but generally refers to establishing a causal relationship between the biological function of a particular protein and pathogenesis; stated in other words, there must be a reasonable expectation that blocking the activity of a target will have a positive, modulating effect on the course of disease.

Target Tractability
Target tractability means that the structure and mechanism of the target make it inherently vulnerable to inhibition by small, drug-like molecules. In other words, the target contains an appropriate drug-binding pocket and is hence deemed “druggable.”

Unmet Patient Need
The third criterion of unmet patient need is self-explanatory, meaning that drug-seeking efforts should be focused on providing medicines to those in greatest need.

The molecular basis for epigenetic regulation of gene expression is the chemical modifications (e.g., acetylation, methylation, ubiquitination, etc.) of DNA and proteins that are catalyzed by specific enzymes. These epigenetic enzymes, which we refer to as epizymes (a contraction of the words epigenetics and enzymes from which our company derives its name), are the molecular focus of our drug discovery efforts for two important reasons. First, these enzymes are the critical drivers of epigenetic processing and their activities are often modulated in disease states. Second, enzymes are considered to be the most druggable (i.e., capable of modulation by small molecule therapeutic agents) targets in all of biology.

The ongoing drug discovery efforts at Epizyme are focused on finding and creating small molecules that can safely and selectively block the aberrant action of specific epigenetic enzymes that meet the criteria outlined above in terms of target validation, target tractability and unmet patient need. Indeed, the precedent set by the clinical success of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors for cancer treatment, portend significant clinical utility for drugs based on inhibition of other epigenetic enzymes. These exciting new drugs represent merely the tip of the iceberg with respect to the potential of inhibitors of epigenetic enzymes for the treatment of human diseases.

Figure 1 – Table of histone deacetylase (HDAC) inhibitors and DNA methyltransferase inhibitors for cancer treatment.