Design and synthesis of enediyne chimeras for targeted degradation of PD-L1.

A substantial fraction of human proteins, including secreted and membrane-localized species, are linked to diseases such as cancer and neurodegeneration upon overexpression or misfolding. However, state-of-the-art targeted protein degradation (TPD) strategies targeting these proteins face limitations such as the "hook" effect and interference with normal cell function. Recently, we developed Protein-Radical-Oxidation Targeting Enediyne Chimeras (PROTECs), a TPD platform that employs an enediyne warhead to directly degrade target proteins without requiring cellular organelles for protein degradation. To extend the application scenarios of PROTECs to the extracellular environment, we herein designed Compound-1, a PROTEC molecule incorporating a PD-L1-targeting ligand (BMS-57), an intrinsic enediyne degradation warhead, and sulfate-based hydrophilicity-adjusting groups to enforce extracellular localization. Compound-1 induced potent and selective degradation of membrane PD-L1 in HeLa cells, achieving a half-maximal degradation concentration (DC) of 44 nM, independent of both proteasomal and lysosomal activity. Furthermore, the targeted PD-L1 degradation reversed tumor immune evasion and enhanced cancer cell killing by peripheral blood mononuclear cells. This study establishes the PROTEC platform as a robust and modular strategy for degrading membrane-associated and extracellular disease-relevant proteins.