Synthesis of Immunoproteasome N‐Degron Prodrugs for Selective Protein Degradation

Targeted protein degradation using bifunctional molecules like proteolysis targeting chimeras (PROTACs) has revolutionized drug discovery but remains limited by E3 ligase availability and lack of cell selectivity. N‐degron degraders provide a smaller, more drug‐like alternative that harnesses endogenous N‐terminal degradation signals independent of recruited ligases. However, they are prone to proteolysis and lack mechanisms for tissue‐specific activation. To overcome these challenges, we developed a “caged” N‐degron degrader selectively activated by the immunoproteasome (iCP), a proteasome isoform induced in cancer and inflammatory settings. By appending an iCP‐recognition tetrapeptide (Ala‐Thr‐Met‐Trp) capped with a morpholine group to the N‐terminus, we shielded the degron from nonspecific cleavage and enabled selective activation in iCP‐expressing cells. This design improved stability, enhanced degradation potency, and minimized activity in healthy cells. Our findings establish a generalizable strategy to spatially control N‐degron activity through disease‐specific proteolytic environments, advancing safer and more selective protein degradation therapeutics.