Targeted Protein Degradation is Only the Beginning: Targeted Protein Modulation
E3 Ligases: The Body’s Gate Keepers for Protein Modulation
The genome encodes over 600 E3 ligases, and as with any broad class of proteins, each one has a specific function. Currently, the field is largely focused on two E3 ligases, cereblon and VHL. We believe that the functional differences among members of this large class of proteins provide the opportunity for highly innovative drugs. Nurix currently has enabled over 30 E3 ligases in our drug discovery process. E3 ligases have historically been considered undruggable, but our knowledge of the structure and function of E3 ligases allowed us to create DNA-encoded libraries designed for identification of binders with drug-like properties that are useful in the types of protein-protein interactions required to alter ligase function. The ability to both turn up or turn down protein levels is a differentiating feature of Nurix’s technology.
Ligase Inhibitors: The Power of a Pathway
Our ability to identify critical ligases and develop potent ligase inhibitors is one arm of our Targeted Protein Modulation approach to drug discovery. In contrast to Targeted Protein Degraders, which degrade a specific disease-causing protein, ligase inhibitors prevent the degradation and thus raise the level of proteins normally controlled by the target ligase.
3 ligases provide the specificity that drives the cellular machinery to degrade a specific set of proteins at the right time, in the right situation, and in the right tissue. While some E3 ligases are relatively ubiquitous, others are highly restricted based on tissue expression or substrate preference. One example of this specificity is the E3 ligase CBL-B, which functions primarily in immune cells and controls T cell and NK cell activation. Given its functional role, we have chosen CBL-B as our first target for ligase inhibition .