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.