2025/01/01 by Renyu Guo, Fukang Yang, Emily C. Cherney · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · #Protein Degradation and Inhibitors #Ubiquitin and proteasome pathways #Peptidase Inhibition and Analysis
paper · pdf · doi:10.1039/d4md00718b
openalex publication_date 2025/01/01 · openalex created_date 2025/02/13 · openalex updated_date 2026/07/16
The ubiquitin proteasome system (UPS) has been successfully hi-jacked by both bifunctional and monovalent small molecules to affect the degradation of proteins that were once considered undruggable. This field has primarily focused on the targeted recruitment of proteins to substrate receptors on E3 ubiquitin ligases, which are only one part of the UPS. More recently, the field has begun to explore recruitment to other types of UPS proteins including E2 ubiquitin-conjugating enzymes, substrate adaptor proteins within the E3 complex, chaperone proteins that associate with E3s, proteasomal subunits, and proteasome-associated proteins. While these approaches are relatively nascent compared to more traditional E3 substrate receptor-based degradation, these approaches are starting to show promise and could offer unique advantages. This review will cover key findings in small molecule UPS-mediated targeted protein degradation (TPD) affected by co-opting proteins beyond traditional E3 substrate receptors.