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.