DELigase

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.