Rational Design of Bioorthogonally Activatable PROTAC for Tumor-Targeted Protein Degradation.

Protein degradation mediated by the proteolysis-targeting chimera (PROTAC) has emerged as an efficient strategy to accurately control intracellular protein levels. However, the development of PROTACs is limited by their systemic toxicity. Herein, we report a bioorthogonally activatable prodrug (BT-PROTAC) strategy to accurately control the activity of PROTACs. As a proof of concept, we introduced the highly reactive trans-cyclooctene into PROTAC molecule MZ1, the structure-acitivity relationships of which were well characterized previously, to construct the bioorthogonally activatable prodrug BT-PROTAC. Compared with MZ1, BT-PROTAC is incapable of degradation of BRD4 protein. However, BT-PROTAC can be activated by highly active tetrazine compound BODIPY-TZ in vitro. Furthermore, we could selectively degrade BRD4 protein in tumor tissue enabled by tumor-targeted tetrazine compound IR808-TZ. This strategy may represent an alternative to existing strategies and may be widely applied in the design of BT-PROTAC targeting other proteins.