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Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells

文献类型：期刊论文

作者Li, Yang6; Zhu, Yuyuan2,5; Shang, Fan-Fan6; Xu, Lin4,6; Jiang, Defang2,5; Sun, Bin4,6; Zhang, Lei4; Luo, Cheng2,5; Zhang, Ao6; Zhang, Hao3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-04-29
卷号67期号:9页码:7176-7196
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00023
通讯作者Zhang, Hao(zhanghao@shutcm.edu.cn) ; Ding, Chunyong(chunding@sjtu.edu.cn)
英文摘要Peroxiredoxin (PRDX1) is a tumor-overexpressed antioxidant enzyme for eliminating excessive reactive oxygen species (ROS) to protect tumor cells from oxidative damage. Herein, a series of celastrol urea derivatives were developed based on its cocrystal structure with PRDX1, with the aim of pursuing a PRDX1-specific inhibitor. Among them, derivative 15 displayed potent anti-PRDX1 activity (IC50 = 0.35 mu M) and antiproliferative potency against colon cancer cells. It covalently bound to Cys-173 of PRDX1 (K-D = 0.37 mu M), which was secured by the cocrystal structure of PRDX1 with an analogue of 15 while exhibiting weak inhibitory effects on PRDX2-PRDX6 (IC50 > 50 mu M), indicating excellent PRDX1 selectivity. Treatment with 15 dose-dependently decreased the mitochondria membrane potential of SW620 cells, probably due to ROS induced by PRDX1 inhibition, leading to cell apoptosis. In colorectal cancer cell xenograft model, it displayed potent antitumor efficacy with superior safety to celastrol. Collectively, 15 represents a promising PRDX1 selective inhibitor for the development of anticolorectal cancer agents.
WOS关键词INDUCE DIFFERENTIATION ; APOPTOSIS ; ACTIVATION ; ROLES
资助项目National Natural Science Foundation of China[22177068] ; National Natural Science Foundation of China[21877120] ; National Natural Science Foundation of China[81903538] ; National Natural Science Foundation of China[21ZR1429100] ; Science and Technology Commission of Shanghai Municipality[2022YFF1203005] ; National Key R&D Program of China[ZYYCXTD-D-202004] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[AF1700037] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[WF220217002] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[WH101117001] ; National Multidisciplinary Innovation Team of Traditional Chinese Medicine[WF540162618] ; Research Laboratory of Medicinal Chemical Biology & Frontiers on Drug Discovery ; Shanghai Jiao Tong University
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001226330700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311291]  
专题新药研究国家重点实验室
通讯作者Zhang, Hao; Ding, Chunyong
作者单位1.Shanghai Jiao Tong Univ, Zhangjiang Inst Adv Study, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Chem Biol Res Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai 201203, Peoples R China
4.Zunyi Med Univ, Sch Pharmaceut Sci, Zunyi 563000, Guizhou, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Li, Yang,Zhu, Yuyuan,Shang, Fan-Fan,et al. Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(9):7176-7196.
APA Li, Yang.,Zhu, Yuyuan.,Shang, Fan-Fan.,Xu, Lin.,Jiang, Defang.,...&Ding, Chunyong.(2024).Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells.JOURNAL OF MEDICINAL CHEMISTRY,67(9),7176-7196.
MLA Li, Yang,et al."Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells".JOURNAL OF MEDICINAL CHEMISTRY 67.9(2024):7176-7196.

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来源：上海药物研究所

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