Degradation of Abl Utilizing an Immunoproteasome N-Degron Prodrug

Targeted protein degradation is an emerging therapeutic strategy that leverages the cell's natural protein clearance pathways to eliminate proteins of interest (POIs). One common approach involves bifunctional molecules that link an E3 ligase ligand to a POI ligand. However, these large molecules often suffer from poor cell permeability, and expanding ligands to new E3 ligases remains a challenge. As an alternative, we explored the use of N-degrons, single amino acid signals attached to small molecules, to recruit E3 ligases and induce POI ubiquitination and degradation. To enhance tissue selectivity and stability, we developed a caged N-degron degrader incorporating a short peptide sequence recognized by the immunoproteasome (iCP). Using this method, we targeted the Abelson proto-oncogene (Abl). Abl was effectively degraded in cells expressing the iCP, and prolonged degradation at lower concentrations was observed. These findings demonstrate that caging N-degrons offers a promising strategy for improving targeted protein degradation approaches through this mechanism.