Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection

Qian Yu; Lixin Gao; Linhao Xu; Yubing Han; Yu Cao; Jianjun Xi; Yigang Zhong; Linjie Li; Liteng Shen; Jinxin Che; Xiaowu Dong; Chong Zhang; Linghui Zeng; Huajian Zhu; Jiaan Shao; Yizhou Xu; Jia Li; Yubo Zhou; Jiankang Zhang

doi:10.1016/j.bmc.2024.117983

Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection

Bioorg Med Chem. 2024 Dec 1:115:117983. doi: 10.1016/j.bmc.2024.117983. Epub 2024 Oct 31.

Authors

Qian Yu¹, Lixin Gao², Linhao Xu³, Yubing Han⁴, Yu Cao⁵, Jianjun Xi⁵, Yigang Zhong³, Linjie Li⁶, Liteng Shen⁶, Jinxin Che⁶, Xiaowu Dong⁶, Chong Zhang¹, Linghui Zeng¹, Huajian Zhu¹, Jiaan Shao¹, Yizhou Xu⁷, Jia Li⁸, Yubo Zhou⁹, Jiankang Zhang¹⁰

Affiliations

¹ Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang Province, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, Guangdong Province, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, Jiangsu Province, China.
³ Department of Cardiology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, Zhejiang Province, China.
⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, Guangdong Province, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, Zhejiang Province, China.
⁶ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China; Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
⁷ Department of Cardiology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, Zhejiang Province, China. Electronic address: [email protected].
⁸ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, Guangdong Province, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
⁹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, Guangdong Province, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
¹⁰ Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, Zhejiang Province, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China. Electronic address: [email protected].

PMID: 39500271
DOI: 10.1016/j.bmc.2024.117983

Abstract

Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016-8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.

MeSH terms

Animals
Anthraquinones* / chemical synthesis
Anthraquinones* / chemistry
Anthraquinones* / pharmacology
Apoptosis / drug effects
Cell Hypoxia / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Endoplasmic Reticulum Stress / drug effects
Humans
Molecular Structure
Myocytes, Cardiac* / drug effects
Myocytes, Cardiac* / metabolism
Myocytes, Cardiac* / pathology
Proteasome Endopeptidase Complex* / metabolism
Structure-Activity Relationship

Substances

Proteasome Endopeptidase Complex
Anthraquinones