Platform

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.

Combining the Power of DEL With Industry-Leading E3 Ligase Expertise

DELigase Platform

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.

E3 Ligases

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 over 90 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 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

1. Scale

Nurix’s DNA-encoded libraries comprises more than five billion small molecules. Each molecule is tagged with a unique DNA bar code that carries the chemical recipe for how the small molecule was synthesized. As an example, a combinatorial DNA-encoded library made from 1,000 individual chemical building blocks combined in three different synthesis steps would contain one billion molecules (1,000 x 1,000 x 1,000).

2. Screening in complex mixtures

Typical high throughput screens require vast amounts of sample handling and complex assays and equipment. Since we are interested in identifying molecules solely based on binding, we can apply the entire library to a protein or protein complex, wash the unbound molecules away, and identify the molecules that remain bound to the target based on the unique DNA tags. Our DEL screen produces a data-rich output amenable to machine learning techniques which further enhance our understanding of novel chemical space.

3. Finding unique binders

Because we do not screen for a specific activity other than binding, DEL is able to identify a wide range of molecules that interact with the target protein of interest. Some may be competitive inhibitors, some allosteric modulators, and others may be silent binders that have no activity on their own. Any of these types of binders may be used as hooks or harnesses for developing Targeted Protein Degraders.

4. Structure activity relationship

Because the library is so large and the molecules are related based on the arrangement of the building blocks, hits often group and can be visualized as lines through a matrix, representing chemical features. These features provide important structure/function relationships and enable our medicinal chemists to quickly turn hits into drug candidates. We also analyze the data using machine learning to discover potential binders that may exist outside of our physical library.

5. Targeted Protein Degrader construction

When the goal is to degrade a target protein, we construct what we call a bivalent Targeted Protein Degrader. This molecule consists of three distinct portions – an E3 ligase binder (harness), a target protein binder (hook), and a linker that connects the two. Because our DEL compounds contain a DNA sequence linked to the small molecule, our chemists know exactly where to attach the linker in our degrader construction.

Targeted Protein Modulation (TPM): Engaging ligases to treat disease

Nurix is leading the field in Targeted Protein Modulation

Nurix has built a drug discovery engine focused on targeting E3 ligases to modulate protein levels directly and specifically in cells. Targeted Protein Modulation comprises two key modalities: Targeted Protein Degradation, which aims to harness the function of E3 ligases and redirect their activity to degrade disease causing proteins, and Targeted Protein Elevation, which aims to increase the level of desirable proteins by directly inhibiting the specific E3 ligase that regulates its degradation. Nurix has leveraged these two powerful modalities to create a robust pipeline of proprietary and partnered drug development programs.

Nurix Drugs Engage Ligases for Targeted Protein Modulation

TPM = TPD + TPE

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.

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 degradation and thus raise the level of proteins normally controlled by the target ligase.

Degrader-Antibody Conjugates (DACs): Tumor-Specific Delivery of Potent Degraders

Advancing a New Therapeutic Class

DACs represent a next generation of antibody-drug conjugates (ADCs) by combining the catalytic activity of a Targeted Protein Degrader (TPD) with the specificity of an antibody. This new therapeutic modality has the potential for enhanced efficacy and improved safety relative to either technology alone. First, replacing the highly toxic ADC payload with degraders may improve both safety and efficacy. Second, DACs are more selective than traditional degraders because DACs deliver degraders specifically to tumor cells. Thus, by combining degrader technology with ADCs, DACs have the potential to be a next generation alternative to both traditional degraders and current ADCs.