Targeted protein degradation (TPD) has emerged as a powerful strategy to eliminate disease-relevant proteins, yet current approaches remain largely constrained to hijacking ubiquitin ligases. We previously introduced ByeTACs, bifunctional molecules that directly recruit proteins to the proteasome for E-ligase independent degradation. Here, we report “Truly” degraders, a new class of dual-mechanism molecules that combine a ligand for the proteasomal receptor Rpn13 with a ligand for cereblon (CRBN) to simultaneously engage both ubiquitin-independent and ubiquitin-dependent degradation pathways. Structure-guided design identified an optimal linker length that supports efficient substrate processing, with the PEG4 derivative (Truly-4) inducing robust depletion of both Rpn13 and CRBN in several cancer cell types. Remarkably, Truly-4 is the first noncovalent small molecule shown to degrade full-length Rpn13, a target previously approached using covalent or domain-restricted strategies. Mechanistic studies confirmed that degradation of Rpn13 proceeds via CRBN-dependent E3 ligase activity, whereas CRBN degradation occurs through an E-ligase independent process, consistent with a ByeTAC mechanism. Importantly, Truly-4 induces selective cytotoxicity in hematologic and solid cancer cell lines but not in healthy cells, despite comparable Rpn13 depletion, indicating that dual degradation can uncouple target engagement from toxicity. These findings establish a generalizable framework for engineering bifunctional degraders that program the proteasome to execute parallel degradation mechanisms and highlight proteasome receptors as druggable nodes for selective destruction of disease-relevant proteins.

New research led by the University of Minnesota Medical School demonstrates that molecules acting as "molecular bumpers" and "molecular glues" can rewire G protein-coupled receptor (GPCR) signaling, turning the cell's busiest receptors into precision tools—opening the door to a new generation of safer, smarter medicines.

Regulator of G protein Signaling 2 (RGS2) negatively modulates signaling downstream of G protein-coupled receptors (GPCRs) by accelerating GTP hydrolysis at Gα subunits of heterotrimeric G proteins. D...

In most drug discovery efforts targeting regulator of G-protein signaling (RGS) proteins, inhibiting their activity is the end-goal. A recent article …

The following column by Senator Todd Young (R-Ind.) and Matthew Pottinger, Former Deputy National Security Advisor of the United States, was published in The Washington Post on March 24, 2025. By Sena...

The development of targeted protein degradation by recruiting a protein of interest to a ubiquitin ligase to facilitate its degradation has become a powerful therapeutic tool. The potential of this approach is limited to proteins that can be readily ubiquitinated and relies on having a ligand with the various E3 ligases. Here, we describe a new methodology for targeted protein degradation that directly recruits a protein of interest to the proteasome for degradation. We generated bifunctional molecules that incorporate a small molecule ligand into a subunit on the 26S proteasome that recruits the protein directly for degradation. ByeTAC degradation requires binding to Rpn-13, a nonessential ubiquitin receptor of the 26S proteasome, and the protein of interest and does not have to rely on the E ligase cascade for ubiquitination. The ByeTAC methodology demonstrates the application of directly recruiting a protein to the proteasome via interactions with Rpn-13 for degradation.

Regulators of G protein signaling (RGS) proteins negatively regulate signaling through G protein-coupled receptors, and reduced RGS protein function i…

Accomplished early-career pharmaceutical scientist recognized as next-generation leader

As researchers representing universities across the country, the last few weeks have been filled with uncertainty. As you are aware, the Trump administration’s National Institutes of Health (NIH) prop...

Regulators of G protein signaling (RGS) proteins finetune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, ki...