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

Abstract

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.

Chemistries of bifunctional PROTAC degraders

“…34). 274 Unlike Zhang's group, the control group they used was (1-methyl-2-nitro-1 H -imidazol-5-yl)methyl and was linked to the E3 ligase ligand VHL. They also found that the degrader 214 can rapidly release the active PROTAC 215 under hypoxia conditions and the activated PROTAC 215 can efficiently induce the degradation of EGFR protein.…”

Enriching Proteolysis Targeting Chimeras with a Second Modality: When Two Are Better Than One

“…A similar hypoxia-activated prodrug strategy was also investigated by Zhu et al in a very recent work. 121 In this case, the authors incorporated a (1-methyl-2-nitro-1 H -imidazol-5-yl)methyl group on the hydroxyl of VHL ligand. Starting from the EGFR-directed PROTAC 40 , they synthesized the PROTAC prodrug 41 ( Figure 15 ), which as a result was unable to degrade EGFR under normoxic conditions.…”

“…A similar hypoxia-activated prodrug strategy was also investigated by Zhu et al in a very recent work . In this case, the authors incorporated a (1-methyl-2-nitro-1 H -imidazol-5-yl)­methyl group on the hydroxyl of VHL ligand.…”

Reactive oxygen species-responsive Pre-PROTAC for tumor-specific protein degradation

“…The inherent microenvironment provides the potential to endogenously release active drugs. 26 Research in this field for PROTAC release is still in the early stages. Recently, hypoxia-activated PROTACs have been reported.…”

“…Recently, hypoxia-activated PROTACs have been reported. 27 Herein, considering the ROS differences between cancerous and normal cells, ROS responsive Pre-PROTACs were designed. We envisioned that these ROS-activated Pre-PROTACs would efficiently degrade the target proteins in cancer cells and have little effect on normal cells due to the elevated ROS levels in cancer cells.…”