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

被引:66
作者
Shi, Shi [1 ]
Du, Yu [2 ]
Zou, Yi [1 ]
Niu, Jing [1 ]
Cai, Zeyu [2 ]
Wang, Xiaonan [2 ]
Qiu, Feihuang [2 ]
Ding, Yi [2 ]
Yang, Gengchen [2 ]
Wu, Yunze [2 ]
Xu, Yungen [1 ,2 ]
Zhu, Qihua [1 ,2 ]
机构
[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China
[2] China Pharmaceut Univ, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 211198, Peoples R China
关键词
PROTEIN-DEGRADATION; FLUORESCENT-PROBE; HYPOXIA; UBIQUITINATION; ACTIVATION; MOLECULES; PRODRUGS; GROWTH;
D O I
10.1021/acs.jmedchem.1c02221
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. Compound17-1was the firstNTR-responsive PROTAC synthesized by incorporating the caging group on the Von Hippel-Lindau (VHL) E3 ubiquitin ligaselig and. It could be activated by NTR to release the active PROTAC17to 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
引用
收藏
页码:5057 / 5071
页数:15
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