Targeted Protein Elevation (TPE): Raising Protein Levels to Control Cellular Pathways
E3 Ligases: The Body’s Gate Keepers for Protein Modulation
The genome encodes over 600 E3 ligases. E3 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.
Targeting E3 Ligases
E3 ligases have historically been considered undruggable, but our knowledge of the structure and function of E3 ligases along with 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.