Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome

被引：13

作者：

Dai, Zhen ^{[1
,2
]}

An, Lu-Yan ^{[1
,2
]}

Chen, Xiao-Yi ^{[1
,2
]}

Yang, Fan ^{[1
,2
]}

Zhao, Ni ^{[1
,2
]}

Li, Cui-Cui ^{[1
,2
]}

Ren, Ren ^{[1
,2
]}

Li, Bing-Yan ^{[1
,2
]}

Tao, Wei-Yan ^{[1
,2
]}

Li, Pei ^{[1
,2
]}

Jiang, Cheng ^{[1
,2
]}

Yan, Fang ^{[1
,2
]}

Jiang, Zheng-Yu ^{[1
]}

You, Qi-Dong ^{[1
]}

Di, Bin ^{[1
,2
]}

Xu, Li-Li ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Key Lab Drug Qual Control & Pharmacovigilance, Minist Educ, Nanjing 210009, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 06期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

NRF2; ACTIVATORS; CRYSTAL-STRUCTURE; EMERGING ROLE; IDENTIFICATION; INHIBITOR; PATHWAY; DISCOVERY; CELLS; POTENT; CORE;

D O I：

10.1021/acs.jmedchem.1c02210

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

1,2,4-Oxadiazole derivatives, a class of Nrf2-AREactivators, exert an extensive therapeutic effect on inflammation, cancer, neurodegeneration, and microbial infection. Among theseanalogues,DDO-7263is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precisemechanism. In this work, we obtained compound7, a mimic ofDDO-7263, and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities toDDO-7263,including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects. Affinity chromatog-raphy and mass analysis techniques revealed Rpn6 as the potential target protein regulating the Nrf2 signaling pathway. In vitro affinity experiments further confirmed thatDDO-7263upregulated Nrf2 through binding to Rpn6 to block the assembly of 26Sproteasome and the subsequent degradation of ubiquitinated Nrf2. These results indicated that Rpn6 is a promising candidate target to activate the Nrf2 pathway for protecting cells and tissues from oxidative, electrophilic, and exogenous microbial stimulation

引用

页码：5029 / 5043

页数：15