Design and Application of Cereblon-Recruiting Prodegraders

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Cereblon (CRBN) is a key E3 ligase substrate receptor in targeted protein degradation (TPD).
• Glutarimide rings are conserved in many CRBN-recruiting ligands, limiting structural diversity.
• Biological glutarimide formation occurs via glutamine cyclization.

Purpose of the Study:

• To develop novel CRBN-recruiting prodegraders by replacing glutarimide with glutamine analogs.
• To investigate the tunability of degradation kinetics and efficacy.
• To establish a generalizable conjugation strategy for CRBN degraders in targeted drug delivery.

Main Methods:

• Synthesis of CRBN-recruiting prodegraders with uncyclized glutamine analogs.
• In cellulo assessment of prodegrader cyclization and target protein degradation (GSPT1).
• Optimization of prodegrader scaffolds for tunable degradation kinetics.
• Conjugation of prodegraders to stimulus-sensitive linkers (photolabile, cathepsin-cleavable).

Main Results:

• Prodegraders successfully underwent in cellulo cyclization, leading to GSPT1 degradation.
• Degradation kinetics and efficacy were tunable, with optimized prodegraders matching parent degrader performance.
• The prodegrader scaffold facilitated conjugation to stimulus-sensitive groups and DAC linkers.
• A generalizable conjugation strategy for CRBN degraders was established, simplifying drug delivery system development.

Conclusions:

• Glutamine analogs can serve as effective CRBN-recruiting prodegraders.
• This strategy allows for tunable degradation and versatile conjugation for targeted drug delivery.
• Prodegraders offer a promising platform for advancing TPD and developing novel therapeutic strategies.