Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Delivery

Background:

• Cereblon (CRBN)-recruiting proteolysis-targeting chimeras (PROTACs) are advanced targeted protein degraders.
• Developing prodrug strategies for CRBN-PROTACs presents significant chemical challenges for effective delivery.

Purpose of the Study:

• To establish generalizable synthetic approaches for creating CRBN-PROTAC prodrugs.
• To demonstrate tunable release kinetics of PROTACs from macromolecular prodrug scaffolds.

Main Methods:

• Developed three orthogonal synthetic strategies: triazole quaternization, tertiary-amine alkylation, and hydroxyl linker installation.
• Incorporated self-immolative linkers with predictable cleavage kinetics.
• Constructed PEGylated macromonomer and bottlebrush prodrug scaffolds.

Main Results:

• Achieved chemoselective and high-yielding syntheses of CRBN-PROTAC prodrugs.
• Demonstrated predictable tuning of PROTAC release rates from macromolecular scaffolds.
• PROTAC-bottlebrush prodrugs showed potency profiles correlating with designed PROTAC release in multiple myeloma models.

Conclusions:

• Established versatile methods for synthesizing CRBN-PROTAC prodrugs.
• Expanded the synthetic possibilities for targeted protein degradation.
• Provided new design principles for controlling degrader activation, selectivity, and in vivo delivery.