scholarly journals ZJ01, a Small Molecule Inhibitor of the Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Protein-Protein Interaction, Reduces Hyperoxic Acute Lung Injury in a Mouse Model

2020 ◽  
Vol 26 ◽  
Author(s):  
Jun Wan ◽  
Shaoyan Lin ◽  
Xiuling Huang ◽  
Qianqin Li ◽  
Lingjun Zeng ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Small Molecule ◽  
Protein Interaction ◽  
Related Factor ◽  
Nuclear Factor ◽  
Protein Protein Interaction ◽  
Molecule Inhibitor ◽  
Nrf2 Protein

scholarly journals Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

2013 ◽  
Vol 23 (10) ◽  
pp. 3039-3043 ◽  
Author(s):  
Longqin Hu ◽  
Sadagopan Magesh ◽  
Lin Chen ◽  
Lili Wang ◽  
Timothy A. Lewis ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitor ◽  
Protein Protein Interaction ◽  
Molecule Inhibitor ◽  
Nrf2 Protein

scholarly journals Novel Keap1-Nrf2 Protein-protein interaction inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome mouse model

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004572021
Author(s):  
Shota Kaseda ◽  
Yuya Sannomiya ◽  
Jun Horizono ◽  
Jun Kuwazuru ◽  
Mary Ann Suico ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protein Interaction ◽  
Alport Syndrome ◽  
Covalent Binding ◽  
Renal Tissue ◽  
Negative Regulator ◽  
Therapeutic Drug ◽  
Related Factor ◽  
Protein Protein Interaction ◽  
Nrf2 Protein

Background　Bardoxolone methyl activates nuclear factor erythroid 2 related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein-1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of Bardoxolone methyl show promising effects for patients with chronic kidney disease (CKD). But the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods　We developed a non-covalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on progressive phenotype in Alport syndrome mouse model (Col4a5-G5X). Results　 Similar to Bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation and fibrosis, and prolonged the lifespan of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in renal tissue of Alport mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Conclusions　UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and presents a potential therapeutic drug for CKD.

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