Generalizable Strategies for the Synthesis of Cereblon‐Recruiting PROTAC Prodrugs

Cereblon (CRBN)‐recruiting PROTACs (proteolysis‐targeting chimeras) are among the most clinically advanced degraders but remain challenging to chemically modify for translation to prodrug‐based delivery strategies. Here, we report three orthogonal approaches—triazole quaternization, tertiary‐amine alkylation, and installation of a hydroxyl linker—that enable chemoselective, high‐yielding syntheses of CRBN‐recruiting PROTAC prodrugs. These strategies allow incorporation of self‐immolative linkers whose cleavage kinetics can be predictably tuned to release the parent PROTAC, which is demonstrated in the context of PEGylated macromonomer and bottlebrush prodrug macromolecular scaffolds. In multiple myeloma models, representative PROTAC‐bottlebrush prodrugs (PROTAC‐BPDs) induce cellular potency profiles that follow the designed PROTAC release rates, confirming that the observed protein degradation and cytotoxicity arise from effective prodrug linker cleavage. Collectively, this work establishes generalizable approaches for constructing prodrugs of CRBN‐based PROTACs, expanding the synthetic space for targeted protein degradation and providing new design principles for controlling degrader activation, selectivity, and in vivo delivery.