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Discovery of GPX4 inhibitors through FP-based high-throughput screening

文献类型：期刊论文

作者Cao, Yu; Wu, Bin9; Xu, Ying5,7; Wang, Mingchen2,3,5; Wu, Xinyu5; Liang, Xiaochen5,7; Lin, Jin9; Li, Zhihai2; Lin, Hua1,4,5; Luo, Cheng4,5,6,8
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-02-05
卷号265页码:14
ISSN号0223-5234
关键词GPX4 inhibitor HTS assay Ferroptosis Fluorescence polarization
DOI10.1016/j.ejmech.2023.116044
通讯作者Lin, Hua(hlin@fjnu.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Chen, Shijie(shijiechen@simm.ac.cn)
英文摘要Ferroptosis is a form of non-apoptotic cell death, regulated by phospholipid hydroperoxide glutathione peroxidase 4 (GPX4), a selenoprotein with a selenocysteine residue (sec) in the active site. GPX4 is a promising target for cancer cells in therapy-resistant conditions via ferroptosis, which can reduce the level of lipid reactive oxygen species (ROS). So far, all existing GPX4 inhibitors covalently bind to GPX4 via a reactive alkyl chloride moiety or masked nitrile-oxide electrophiles with poor selectivity and pharmacokinetic properties and most were obtained by cell phenotype-based screening. Lacking of effective high-throughput screening methods for GPX4 protein limits the discovery of GPX4 inhibitors. Here, we report a fluorescence polarization (FP)-based high throughput screening (HTS) assay for GPX4-U46C-C10A-C66A in vitro, and found Metamizole sodium from our in-house compound library inhibits GPX4-U46C-C10A-C66A enzyme activity. Structure-activity relationships (SAR) demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46CC10A-C66A. Our FP assay could be an effective tool for discovery of GPX4 inhibitors and Metamizole sodium was a potential inhibitor for GPX4 in vitro.
WOS关键词CELL-DEATH ; CANCER-CELLS
资助项目National Centre for Protein Science Shanghai (Protein Expression and Purification system) ; National Key Research and Development Program of China[2022YFC2804800] ; National Key R & D Program of China[2022YFC3400500] ; National Key R & D Program of China[2021ZD0203900] ; Science and Technology Commission of Shanghai Municipality[21ZR1474700] ; Youth Innovation Promotion Association of CAS[2022279] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[92253303] ; National Natural Science Foundation of China[22377013] ; Fujian Provincial Natural Science Foundation[2021J01203] ; State Key Laboratory of Drug Research[SKLDR-2023-KF- 07] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine - National Administration of Traditional Chinese Medicine[ZYYCXTD-202004] ; High -level new R D institute[2019B090904008] ; High -level Innovative Research Institute, Department of Science and Technology of Guangdong Province[2021B0909050003]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001146830100001
源URL[http://119.78.100.183/handle/2S10ELR8/308790]  
专题中国科学院上海药物研究所
通讯作者Lin, Hua; Luo, Cheng; Chen, Shijie
作者单位1.Fujian Normal Univ, Fujian Prov Univ, Coll Life Sci, Key Lab Innate Immune Biol Fujian Prov,Key Lab Mic, Fuzhou 350117, Peoples R China
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Drug Discovery & Design Ctr,State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
7.China Pharmaceut Univ, Nanjing 210009, Peoples R China
8.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
9.Fujian Med Univ, Sch Pharm, Fuzhou 350122, Peoples R China
推荐引用方式
GB/T 7714		 Cao, Yu,Wu, Bin,Xu, Ying,et al. Discovery of GPX4 inhibitors through FP-based high-throughput screening[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,265:14.
APA Cao, Yu.,Wu, Bin.,Xu, Ying.,Wang, Mingchen.,Wu, Xinyu.,...&Chen, Shijie.(2024).Discovery of GPX4 inhibitors through FP-based high-throughput screening.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,265,14.
MLA Cao, Yu,et al."Discovery of GPX4 inhibitors through FP-based high-throughput screening".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 265(2024):14.

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来源：上海药物研究所

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