Design, synthesis and evaluation of novel small molecules acting as Keap1-Nrf2 protein-protein interaction inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 37; no. 1; pp. 2575 - 2588
• Main Authors: Sun, Yunfeng, Zheng, Lulu, Yang, Bo, Ge, Shuyu, Li, Qiang, Zhang, Mingwan, Shen, Shenghui, Ying, Yin
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 31.12.2022; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: Ames test; Biochemistry & Molecular Biology; Chemistry, Medicinal; Chinese medicine; Chloride; drug design; Gene expression; Heart diseases; Hydrocarbons; Inflammation; inflammatory response; Keap1-Nrf2 PPI inhibitor; Life Sciences & Biomedicine; Lipopolysaccharides; Metabolism; Myocarditis; Naphthalene; NRF2 protein; Organic chemicals; Original; Oxidative stress; Pharmacology & Pharmacy; Pharmacy; Protein interaction; Proteins; Reactive oxygen species; Science & Technology; synthesis; synthesis; ASSAY; NRF2; Keap1-Nrf2 PPI inhibitor; drug design; myocarditis; inflammatory response; CHEMISTRY; IDENTIFICATION; DERIVATIVES; oxidative stress; DISCOVERY
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2022.2124408

Direct interference with Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) has recently been introduced as an attractive approach to control life-threatening diseases like myocarditis. The present study aimed to investigate the potential application in myocarditis of a series of novel non-naphthalene derivatives as potential Keap1-Nrf2 PPI inhibitors. Our results indicated that the optimal compound K22 displayed the highest metabolic stability and showed notable Keap1-Nrf2 PPI inhibitory activities in vitro. K22 effectively triggered Nrf2 activation and increased the protein and mRNA expression of Nrf2-regulated genes in H9c2 cells. Moreover, pre-treatment with K22 was shown to mitigate LPS-induced damage to H9c2 cells, causing a marked decrease in the levels of inflammatory factors as well as reactive oxygen species (ROS). Furthermore, K22 was also shown to be non-mutagenic in the Ames test. Overall, our findings suggest that K22 may be a promising drug lead as a Keap1-Nrf2 PPI inhibitor for myocarditis treatment.