Combining the Power of DEL With Industry-Leading E3 Ligase Expertise
Our DELigase platform, which enables our robust drug discovery pipeline, relies on two underlying features – our collection of E3 ligases and our DNA-encoded libraries of small molecules. Our platform is highly differentiated and allows us to identify small molecules that can either decrease or increase protein levels – processes we refer to as Targeted Protein Modulation.
The genome encodes over 600 E3 ligases, each one with a specific function. Currently, the field is largely focused on two E3 ligases, cereblon and VHL. We have enabled 60 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 specifically designed to identify drugs that harness or inhibit E3 ligases.
DNA-Encoded Library (DEL)
Our DNA-encoded library is a large collection of more than five billion molecules, each tagged with a unique DNA bar code. The DEL is screened as a mixture to identify molecules that bind a given protein target, and the DNA tag allows trace amounts of a molecule to be identified using DNA sequencing technologies. We use our DEL to find binders for both target proteins and E3 ligases, providing the key starting materials for our Targeted Protein Modulation process. There are several advantages of Nurix’s DEL for both drugging difficult targets and constructing Targeted Protein Degraders.
DNA-Encoded Library (DEL)
Our DNA-encoded library is a large collection of more than five billion molecules, each tagged with a unique DNA bar code. The DEL is screened as a mixture to identify molecules that bind to a given protein target, and the DNA tag allows trace amounts of a molecule to be identified using DNA sequencing technologies. Nurix uses its DEL to find binders for both target proteins and E3 ligases, providing the key starting materials for its Targeted Protein Modulation process. There are several advantages of Nurix’s DELigase approach for drugging difficult targets such as ligases for the purpose of Targeted Protein Elevation and constructing Targeted Protein Degraders.
The power of DEL: A powerful and efficient screen to find unique binders to target proteins and to E3 ligases
2. Screening in complex mixtures
3. Finding unique binders
4. Structure activity relationship
5. Targeted Protein Degrader construction
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 structure of a Targeted Protein Degrader has three distinct regions: the E3 ligase binder (harness), the target protein binder (hook), and the linker.
Targeted Protein Degraders have several potential advantages over traditional small molecule inhibitors:
1. Catalytic degradation
2. Prolonged activity
3. Complete elimination of target function
4. Oral administration
5. Activity against resistant mutations
6. Drugging the undruggable
Targeted Protein Elevation: Raising Protein Levels to Control Cellular Pathways
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 60 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 increase or decrease protein levels is a differentiating feature of Nurix’s technology.
Targeting E3 Ligases
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.
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 .
Nurix Adoptive Cell Therapy (NxACT)
Drug-Enhanced Cell Therapy to Improve Patient Outcomes
Targeted Protein Modulation can improve the expansion and quality of cell therapy products, and Nurix is pursuing its drug-enhanced cell therapies under our Nurix Adoptive Cell Therapy or NxACT approach. The first and most advanced NxACT approach is drug-enhanced tumor infiltrating lymphocytes (DeTIL). Our lead cell therapy program called DeTIL-0255 uses our proprietary ex vivo CBL-B inhibitor, NX-0255, to enhance the activity of tumor infiltrating lymphocytes.
Nurix is pursuing internal development of DeTIL-0255 as its lead DeTIL program. More on DeTIL