UBIQUITIN LIGASES OVERVIEW

MODULATING UBIQUITIN LIGASE FUNCTION

ADVANCED E3 UBIQUITIN LIGASE & E2 CONJUGATING ENZYME SCIENCE

Nurix is pioneering rational drug design in the emerging field of protein regulation by targeting E2 conjugating enzymes and E3 ligases that control the Ubiquitin Proteasome System (UPS).

Regulation of protein stability by the UPS is modulated by the activity of these E2 and E3 enzymes, which control the tagging of proteins with ubiquitin for degradation by the proteasome. The human genome encodes approximately 1,000 different E3 ligases and 60 E2 enzymes. A number of these ligases recently have been shown to play key roles in human diseases, particularly in cancer and autoimmune disease.

Although discovered prior to scientific understanding of the central role of the UPS in cellular metabolism, highly successful drugs such as Velcade®, Kyprolis® and Revlimid® have been found to act through modulation of the UPS. Velcade® and Kyprolis® are 26S proteasome inhibitors and Revlimid® is a modulator of cereblon, an E3 ligase. And yet, notably, these products target only two of the multitude of UPS pathways now available for drug discovery.

Nurix’s Protein Regulation Platform unlocks the E3 and E2 enzyme class of targets for important medical breakthroughs by using a combination of proprietary screens, insights from structural biology, and our unique Molecular Glue chemistry to develop a class-wide drug discovery advantage.

 

 
The ability to positively or negatively regulate the UPS is the foundation of Nurix technology.
 

 

TO be or not to be...

The ability of the UPS to regulate protein function positively or negatively is the foundation of Nurix technology. Our proprietary Molecular Glue chemistry delivers selective compounds that can enhance protein-protein binding at previously unappreciated binding sites in the E3 ligase-substrate interface to stimulate protein ubiquitylation and subsequent degradation.

Our Protein Regulation Platform also can produce drug candidates that inhibit specific interactions between ubiquitin ligases and their protein substrates. Our detailed structural and biochemical understanding of the binding of ligase enzymes and their substrates reveals key areas where small molecules may specifically disrupt these interactions.

 

To SELECTIVEly CONTROL THE FUNCTION OF ONCOGENES AND TUMOR SUPPRESSORS

Some tumors have altered regulation of the UPS that prevents degradation of proteins encoded by oncogenes that drive tumor cell growth. This dysregulation can be caused by specific mutations at the interface of an E3 ligase and its oncogenic substrate. We apply our proprietary Molecular Glue chemistry to identify compounds that selectively re-engage the UPS to target these harmful proteins. The growing database of tumor-specific mutations thus can be harnessed to identify driver mutations that dysregulate the UPS system, providing great potential for the discovery of breakthrough cancer therapeutics.

Conversely, some tumors hyper-activate particular ubiquitin ligases through gene amplification or over-expression, triggering inappropriate degradation of protective tumor suppressor proteins. In such cases, our Protein Regulation Platform can identify selective inhibitors of these ligases in order to restore tumor suppressor activity.

 

TO UNLEASH THE IMMUNE SYSTEM TO FIGHT CANCER THROUGH IMMUNO-ONCOLOGY

We also are applying our Protein Regulation Platform to discover selective modulators of certain E3 ligases that have been identified as checkpoints for the immune system. Combining regulation of the UPS with the amplifying power of immune surveillance holds the potential to discover a new class of small molecule drugs delivering controlled immune therapy for cancer.