Rational Design for Nitroreductase (NTR)-Responsive Proteolysis Targeting Chimeras (PROTACs) Selectively Targeting Tumor Tissues

The
catalytic properties of proteolysis targeting chimeras (PROTACs)
may lead to uncontrolled off-tissue target degradation that causes
potential toxicity, limiting their clinical applications. The precise
control of this technology in a tissue-selective manner can minimize
the potential toxicity. Hypoxia is a hallmark of most solid tumors,
accompanied by elevated levels of nitroreductase (NTR). Based on this
character, we presented a type of NTR-responsive PROTACs to selectively
degrade proteins of interest (POI) in tumor tissues. Compound 17-1 was the first NTR-responsive PROTAC synthesized by incorporating
the caging group on the Von Hippel–Lindau (VHL) E3 ubiquitin
ligase ligand. It could be activated by NTR to release the active
PROTAC 17 to efficiently degrade the EGFR protein and
subsequently exert antitumor efficacy. Thus, a general strategy for
the precise control of PROTAC to induce POI degradation in tumor tissues
by NTR was established, which provided a generalizable platform for
the development of NTR-controlled PROTACs to achieve selective degradation.