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Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening

文献类型：期刊论文

作者Chen, Shuang6,7; Wang, Zhenyu5,7; Gao, Jia6,7; Wang, Yanlin4,6; Liang, Jiayin3,6; Zhu, Yingshuang3,6; Xu, Heng5; Chen, Kaixian5,7; Jin, Lu6; Zhang, Hao1,2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-06-23
卷号68期号:13页码:13609-13627
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00433
英文摘要Celastrol has been identified as a reactive oxygen species (ROS) elevator that reduces cancer cell proliferation by inhibiting peroxiredoxin (PRDX) activity, albeit with poor selectivity. We describe a semiautomated and microplate-based parallel compound library approach leading to the rapid discovery of celastrol derivatives that are potent and selective PRDX1 inhibitors. Amide coupling and the urea bond forming reactions were used to construct a 2720-member celastrol derivative library, followed by in situ PRDX1 enzyme inhibition assay screening, leading to the rapid identification of a series of celastrol derivatives demonstrating promising PRDX1 inhibition activity. Compound LC-PDin06 displayed the best anti-PRDX1 activity (IC50 = 0.042 mu M) with selectivity toward the PRDX family, as well as good antiproliferative activity against colorectal cancer cells. A cocrystal structure of PRDX1 with LC-PDin20 and molecular docking studies provided insight into the binding mode of the inhibitors with PRDX1, aiding in the structure-based design of future PRDX1 inhibitors.
WOS关键词INDUCE DIFFERENTIATION ; PEROXIREDOXIN I ; CANCER ; ROS ; IDENTIFICATION ; ANTIOXIDANTS ; MECHANISMS ; APOPTOSIS ; SYSTEM ; TARGET
资助项目National Natural Science Foundation of China ; National Centre for Protein Science Shanghai (Protein Expression and Purification system)[82304301] ; National Centre for Protein Science Shanghai (Protein Expression and Purification system)[81903538] ; National Centre for Protein Science Shanghai (Protein Expression and Purification system)[82104064] ; National Natural Science Foundation of China[2023B2030] ; National Natural Science Foundation of China[CXTD2023010] ; Zhongshan Municipal Bureau of Science and Technology[ZIDD202302] ; Zhongshan Institute for Drug Discovery[2019B090904008] ; High-level new RD institute[XDB0830000] ; Chinese Academy of Sciences[2021B0909050003] ; High-level Innovative Research Institute[2021B1515420002] ; Guangdong Basic and Applied Basic Research Foundation[24JS2830200] ; Guangdong Basic and Applied Basic Research Foundation[22ZR1474200] ; Science and Technology Commission of Shanghai Municipality
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001514113400001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/318489]  
专题新药研究国家重点实验室
通讯作者Jin, Lu; Zhang, Hao; Xiong, Huan
作者单位1.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Shanghai 201203, Peoples R China
2.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China
3.Guangzhou Univ Chinese Med, Guangzhou 510006, Guangdong, Peoples R China
4.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Shuang,Wang, Zhenyu,Gao, Jia,et al. Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(13):13609-13627.
APA Chen, Shuang.,Wang, Zhenyu.,Gao, Jia.,Wang, Yanlin.,Liang, Jiayin.,...&Luo, Cheng.(2025).Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening.JOURNAL OF MEDICINAL CHEMISTRY,68(13),13609-13627.
MLA Chen, Shuang,et al."Rapid Discovery of Celastrol Derivatives as Potent and Selective PRDX1 Inhibitors via Microplate-Based Parallel Compound Library and In Situ Screening".JOURNAL OF MEDICINAL CHEMISTRY 68.13(2025):13609-13627.

入库方式： OAI收割

来源：上海药物研究所

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