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.

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, a process 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 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 specifically designed to identify drugs that harness or inhibit E3 ligases.

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. 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 DEL for 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 DEL for drugging difficult targets 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. If the library was made from 1,000 individual chemical building blocks combined in three different synthesis steps, then the total number of molecules in the library will be 1,000 x 1,000 x 1,000 or five billion.

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 bind 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. CTM construction

When the goal is to degrade a target protein, we construct what we call a Chimeric Targeting Molecule (CTM). 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 CTM construction.

Targeted Protein Degradation: 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. Because these molecules bind two different proteins simultaneously, we refer to them as Chimeric Targeting Molecules (CTMs). The structure of the CTM has three distinct regions: the E3 ligase binder (harness), the target protein binder (hook), and the linker.

CTMs 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. A CTM catalyzes the degradation of its target, and can do this over and over again, degrading multiple copies of its targets, thus increasing its potency.

2. Prolonged activity

Standard inhibitors are only active while they are bound to a protein’s active site and will fall off over time. CTMs catalyze the degradation of the protein, and the target needs to be resynthesized before it can be active again.

3. Complete elimination of target function

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

4. Oral administration

Given their ability to remove the targeted protein, CTMs are functionally more similar to genetic and RNA knockout or knock-down, which typically require injection or infusion. Our CTMs are designed to be administered orally, once daily.

5. Activity against resistant mutations

Standard inhibitors typically require very high affinity binding, and are susceptible to mutations at their binding site, particularly in cancer and infectious disease targets. CTMs can function with lower affinity binding, and our BTK degraders have demonstrated sustained activity in the presence of certain common resistance mutations.

6. 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 CTMs.

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 .

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 focusing on applying it in two ways under our Nurix Adoptive Cell Therapy or NxACT approach: drug-enhanced tumor infiltrating lymphocytes (DeTIL) and drug-enhanced chimeric antigen receptor T cells (DeCART). 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.

DeTIL

Nurix is pursuing internal development of DeTIL-0255 as its lead DeTIL program. More on DeTIL