Targeted Protein Degradation Utilizing Rpn-13

Targeting the proteasome-mediated protein degradation pathway in protein accumulation diseases, and a variety of cancer types, has led to the development of a myriad of small molecule therapeutics. While proteasome inhibitors were the initial class of molecules used to modify protein degradation, there has recently been great interest in harnessing the activity of the proteasome to degrade proteins whose activity can be essential for the survival of a diseased cell type. The most well-known class of degraders are called proteolysis targeting chimeras or PROTACs. These are bifunctional molecules that bind a protein of interesting (POI) and an E3 ligase. This leads to the ubiquitination of the POI and degradation by the proteasome. The decrease in levels of the POI, which typically is an oncogenic protein, leads to cell death of the cancerous cell population highly dependent on the activity/expression of the POI. While this is an effective degrader mechanism it would be more optimal to induce an interaction between the proteasome and the POI without being dependent on the ubiquitination via an interaction with an E3. Rpn-13 is one of the two ubiquitin receptors of the proteasome complex and is highly expressed in a number of disease types. It is the non-essential ubiquitin receptor of the proteasome, but diseased or stressed cells express it, in addition to the essential ubiquitin receptor (Rpn-10), to degrade proteins more quickly for survival and proliferation. For this technology development grant, we are proposing to expand upon our recent development of new bifunctional molecules that can elicit degradation of a POI by associating the POI in close proximity to the entrance of the opening of the proteasome by binding Rpn-13. This new class of degraders is not be dependent on the ubiquitination of the POI. These Rpn-13-mediated degraders will be more broadly applicable as there will be no need to discover additional ligands that interact with E3 ligases. There is also a possibility these new degraders could be used to associate the proteasome with larger protein complexes to degrade them through a ubiquitin-independent process. The bifunctional degraders we are proposing to develop and validate in this proposal will provide the first tools to degrade specific POIs through the ubiquitin-independent process. Project Number: 1R01GM163338-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Darci Trader | Institution: UNIVERSITY OF CALIFORNIA-IRVINE, IRVINE, CA | Award Amount: $448,510 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 MBBC-V (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11320622