Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome.
J Med Chem
; 65(6): 5029-5043, 2022 03 24.
Article
em En
| MEDLINE
| ID: mdl-35253427
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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1
Base de dados:
MEDLINE
Assunto principal:
Oxidiazóis
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Fator 2 Relacionado a NF-E2
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article