Advancing Targeted Protein Degradation Through Immunoproteasome‐Caged N‐Degrons

Proteolysis-targeting chimeras (PROTACs) are a promising therapeutic modality that induces the degradation of proteins of interest, yet continue to be limited by metabolic instability and nonoptimal selectivity. N-degron-based PROTACs, while compact and effective recruiters of N-recognins (E3 ubiquitin ligases), are particularly prone to premature degradation and off-target effects. To address this challenge, Loy et al. introduced a "caged" N-degron PROTAC in which a tetrapeptide-morpholine fragment shields the arginine degron. This sequence is specifically recognized by the immunoproteasome (iCP), an inducible proteasome isoform highly expressed in cancer and inflammatory cells, while absent in most healthy tissues. Upon iCP-mediated cleavage, the degron is unmasked, allowing for the degradation of ABL tyrosine kinase via dasatinib-linked PROTAC activity. This protease-gated strategy integrates endogenous proteolytic specificity into degrader activation, enhancing functional stability while allowing context-dependent specificity. Despite these elegant improvements, some challenges remain regarding cell permeability and disease-dependent iCP expression. Nevertheless, immunoproteasome-gated degron represents a compelling framework for the next generation of N-degron PROTACs. Herein, we highlight these recent findings in the context of the design principles, mechanistic insights, and therapeutic implications of this approach and briefly discuss some key challenges and opportunities for future development.