Targeted Protein Degradation

Targeting Virtually Any Protein to Treat Disease

Nurix has leveraged its deep E3 ligase expertise and internally developed DNA-encoded libraries (DEL) to develop its DELigase platform for Targeted Protein Modulation. DELigase can harness the activity of specific E3 ligases to destroy disease-causing proteins, an approach known as Targeted Protein Degradation, or inhibit specific E3 ligases to increase levels of beneficial proteins, an approach we call Targeted Protein Elevation.

Targeted Protein Degradation (TPD): A New Generation of Therapeutics

Drugging the Undruggable

E3 ligases catalyze the transfer of ubiquitin onto a target protein. The presence of the ubiquitin tag destines the protein for destruction by the proteasome. Targeted Protein Degraders are small molecules that simultaneously bind an E3 ligase and a target protein to facilitate the transfer of ubiquitin onto that target protein, thus causing its degradation. The Targeted Protein Degrader is then free to repeat this process, such that each degrader can cause the degradation of multiple target proteins. Given their ability to remove the targeted protein, degraders are functionally more similar to genetic and RNA knockout or knock-down, which typically require injection or infusion. Our degraders are typically designed to be administered orally.

Targeted Protein Degradation

Harnessing the ubiquitin proteosome system to eliminate disease proteins

Targeted Protein Degraders have several potential advantages over traditional small molecule inhibitors:

1. Catalytic degradation

Standard inhibitors only block their target when they are bound to it, and each inhibitor molecule can only inhibit a single target (i.e., occupancy-driven pharmacology). A protein degrader catalyzes the degradation of its target, and can do this over and over again, degrading multiple copies of its targets, thus increasing its potency (i.e., event-driven pharmacology).

2. Sustained activity

Standard inhibitors are effective only when bound to a protein’s active site, and their efficacy diminishes over time as they detach. In contrast, a degrader facilitates the degradation of the protein, requiring the target to undergo resynthesis before becoming active again. This mechanism holds the potential for improved target coverage throughout the dosing period.

3. Elimination of target function(s)

Certain targets have multiple activities. For example, a signaling molecule may have an enzymatic function and a scaffolding function. Standard inhibitors may only disrupt the enzymatic function, leaving other functions uninhibited. A degrader catalyzes the degradation of the target thus eliminating all of its activities.

4. Activity against resistance mutations

Standard inhibitors typically require high affinity binding and continuous occupancy. Consequently, they are susceptible to mutations at their binding site, particularly in cancer and infectious disease targets. In contrast, degraders can function with lower affinity binding through a process known as co-operativity. Our BTK degraders have demonstrated sustained activity in the presence of certain common resistance mutations.

5. Drugging the undruggable

Some disease-causing proteins, such as structural proteins and protein complexes, are not amenable to standard inhibitors. We believe these targets can be addressed using degraders.