Recent advances in small molecule inhibitors of deubiquitinating enzymes

Proteins play a pivotal role in maintaining cellular homeostasis. Their degradation primarily orchestrated through the ubiquitin-proteasome system (UPS) and cellular autophagy. Dysfunction of the UPS is associated with various human diseases, including cancer, autoimmune disorders, and neurodegenerative conditions. Consequently, the UPS has emerged as a promising therapeutic target. Deubiquitinases (DUBs) have garnered significant attention as potential targets for therapeutic intervention due to their role in modulating protein stability and function. This review focuses on recent advancements of DUBs, particularly their relevance in the UPS and their potential as drug targets. Notably, inhibitors targeting specific DUBs, such as USP1, USP7, USP14, and USP30 have shown promise in preclinical and clinical studies for cancer therapy. Additionally, DUB inhibitors have been involved in novel therapeutic approaches lately, including as targets for proteolysis-targeting chimeras (PROTACs) or as tools in deubiquitinase-targeting chimeras (DUBTACs).