Advancing Targeted Protein Degradation Through Immunoproteasome-Caged N-Degrons - PubMed
7 hours ago
- #Immunoproteasome
- #PROTACs
- #Targeted Protein Degradation
- PROTACs are a promising therapeutic modality for targeted protein degradation but face limitations like metabolic instability and selectivity issues.
- N-degron-based PROTACs are compact and effective but prone to premature degradation and off-target effects.
- Loy et al. introduced a 'caged' N-degron PROTAC, shielded by a tetrapeptide-morpholine fragment, specifically recognized by the immunoproteasome (iCP).
- The iCP is highly expressed in cancer and inflammatory cells but absent in most healthy tissues, allowing for context-dependent specificity.
- Upon iCP-mediated cleavage, the degron is unmasked, enabling targeted degradation of ABL tyrosine kinase via dasatinib-linked PROTAC activity.
- This strategy enhances functional stability and integrates endogenous proteolytic specificity into degrader activation.
- Challenges remain regarding cell permeability and disease-dependent iCP expression.
- Immunoproteasome-gated degron represents a compelling framework for next-generation N-degron PROTACs.