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

  • J Med Chem. 2022 Mar 24;65(6):5029-5043. doi: 10.1021/acs.jmedchem.1c02210.
Zhen Dai  1  2 ,  Lu-Yan An  1  2 ,  Xiao-Yi Chen  1  2 ,  Fan Yang  1  2 ,  Ni Zhao  1  2 ,  Cui-Cui Li  1  2 ,  Ren Ren  1  2 ,  Bing-Yan Li  1  2 ,  Wei-Yan Tao  1  2 ,  Pei Li  1  2 ,  Cheng Jiang  1  2 ,  Fang Yan  1  2 ,  Zheng-Yu Jiang  1 ,  Qi-Dong You  1 ,  Bin Di  1  2 ,  Li-Li Xu  1  2
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
PMID: 35253427 DOI: 10.1021/acs.jmedchem.1c02210
Abstract

1,2,4-Oxadiazole derivatives, a class of Nrf2-ARE activators, exert an extensive therapeutic effect on inflammation, Cancer, neurodegeneration, and microbial Infection. Among these analogues, DDO-7263 is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precise mechanism. In this work, we obtained compound 7, a mimic of DDO-7263, and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities to DDO-7263, including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects. Affinity chromatography and mass analysis techniques revealed Rpn6 as the potential target protein regulating the Nrf2 signaling pathway. In vitro affinity experiments further confirmed that DDO-7263 upregulated Nrf2 through binding to Rpn6 to block the assembly of 26S Proteasome 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.

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