1. Academic Validation
  2. Rational Design for Nitroreductase (NTR)-Responsive Proteolysis Targeting Chimeras (PROTACs) Selectively Targeting Tumor Tissues

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

  • J Med Chem. 2022 Mar 24;65(6):5057-5071. doi: 10.1021/acs.jmedchem.1c02221.
Shi Shi 1 Yu Du 2 Yi Zou 1 Jing Niu 1 Zeyu Cai 2 Xiaonan Wang 2 Feihuang Qiu 2 Yi Ding 2 Gengchen Yang 2 Yunze Wu 2 Yungen Xu 1 2 Qihua Zhu 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
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.

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