Three Chemoselective Routes Turn Cereblon PROTACs into Cleavable Prodrugs
- Cereblon-recruiting PROTACs are hard to derivatize for prodrug delivery; the paper offers three orthogonal handles: triazole quaternization, tertiary-amine alkylation and a hydroxyl linker.
- The approaches give cleavable prodrugs with tunable release kinetics, compatible with PEGylated constructs and bottlebrush prodrugs.
- Representative examples showed controlled degrader release, in vitro anticancer activity, tumor accumulation and preliminary in vivo efficacy.
💡 Points
The real PROTAC problem is exposure rather than ternary-complex cooperativity, so a modular way to mask and release them is overdue. Chemoselectivity on a glutarimide-bearing molecule is the practical point: if it works on existing degraders without re-optimization, it is genuinely reusable. I'd check release in plasma versus tumor, and whether the masked forms avoid premature cereblon engagement.
Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs ↗