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

Yunfeng Sun; Lulu Zheng; Bo Yang; Shuyu Ge; Qiang Li; Mingwan Zhang; Shenghui Shen; Yin Ying

doi:10.1080/14756366.2022.2124408

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

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2575-2588. doi: 10.1080/14756366.2022.2124408.

Authors

Yunfeng Sun^{1

2}, Lulu Zheng^{1

2}, Bo Yang^{1

2}, Shuyu Ge^{1

2}, Qiang Li^{1

2}, Mingwan Zhang^{1

2}, Shenghui Shen³, Yin Ying^{1

2}

Affiliations

¹ Department of Pharmacy, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, China.
² Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China.
³ Department of Cardiology, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China.

Abstract

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.

Keywords: Keap1-Nrf2 PPI inhibitor; drug design; inflammatory response; myocarditis; oxidative stress; synthesis.

MeSH terms

Humans
Kelch-Like ECH-Associated Protein 1 / metabolism
Lipopolysaccharides
Myocarditis*
NF-E2-Related Factor 2* / metabolism
RNA, Messenger
Reactive Oxygen Species / metabolism

Substances

KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
Lipopolysaccharides
NF-E2-Related Factor 2
RNA, Messenger
Reactive Oxygen Species

Grants and funding

This research was supported by the Joint Funds of the Zhejiang Provincial Natural Science Foundation of China under Grant No. LQY20H300001 and No. LYY19H310006.