Discovery of chalcone analogues as novel NLRP3 inflammasome inhibitors with potent anti-inflammation activities

Cheng Zhang; Hu Yue; Ping Sun; Lei Hua; Shuli Liang; Yitao Ou; Dan Wu; Xinyi Wu; Hao Chen; Ying Hao; Wenhui Hu; Zhongjin Yang

doi:10.1016/j.ejmech.2021.113417

Discovery of chalcone analogues as novel NLRP3 inflammasome inhibitors with potent anti-inflammation activities

Eur J Med Chem. 2021 Jul 5:219:113417. doi: 10.1016/j.ejmech.2021.113417. Epub 2021 Apr 1.

Authors

Cheng Zhang¹, Hu Yue¹, Ping Sun¹, Lei Hua¹, Shuli Liang¹, Yitao Ou¹, Dan Wu¹, Xinyi Wu¹, Hao Chen¹, Ying Hao¹, Wenhui Hu², Zhongjin Yang³

Affiliations

¹ Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China.
² Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: huwenhui@gzhmu.edu.cn.
³ Key Laboratory of Molecular Target & Clinical Pharmacology and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China. Electronic address: yzj23@gzhmu.edu.cn.

PMID: 33845232
DOI: 10.1016/j.ejmech.2021.113417

Abstract

NLRP3 inflammasome activation plays a critical role in inflammation and its related disorders. Herein we report a hit-to-lead effort resulting in the discovery of a novel and potent class of NLRP3 inflammasome inhibitors. Among these, the most potent lead 40 exhibited improved inhibitory potency and almost no toxicity. Further mechanistic study indicated that compound 40 inhibited the NLRP3 inflammasome activation via suppressing ROS production. More importantly, treatment with 40 showed remarkable therapeutic effects on LPS-induced sepsis and DSS-induced colitis. This study encourages further development of more potent inhibitors based on this chemical scaffold and provides a chemical tool to identify its cellular binding target.

Keywords: Inhibitor; Michael acceptor; NLRP3 inflammasome.

MeSH terms

Animals
Anti-Inflammatory Agents / chemistry*
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Cell Line
Chalcones / chemistry*
Chalcones / metabolism
Chalcones / pharmacology
Chalcones / therapeutic use
Colitis / chemically induced
Colitis / drug therapy
Disease Models, Animal
Drug Design*
Female
Inflammasomes / drug effects
Inflammasomes / metabolism*
Lipopolysaccharides / toxicity
Macrophages / cytology
Macrophages / drug effects
Macrophages / metabolism
Male
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Pyroptosis / drug effects
Reactive Oxygen Species / metabolism
Sepsis / drug therapy
Sepsis / etiology
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Chalcones
Inflammasomes
Lipopolysaccharides
NLR Family, Pyrin Domain-Containing 3 Protein
Reactive Oxygen Species