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Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor

文献类型：期刊论文

作者Zhou, Zhenfei5,6,7,8; Huang, Siqi4,6,7; Fan, Shijie5; Li, Xueyuan3,5; Wang, Chengyu5; Yu, Wanlin3,5; Du, Daohai6,7; Zhang, Yuanyuan4,6,7; Chen, Kaixian4,6,7,8; Fu, Wei8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-16
卷号67期号:14页码:12184-12204
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00898
通讯作者Chen, Kaixian(kxchen@simm.ac.cn) ; Fu, Wei(wfu@fudan.edu.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要Autophagy is a highly conserved cellular homeostasis maintenance mechanism in eukaryotes. Microtubule-associated protein light chain 3 (LC3) plays a crucial role in autophagy. It has multiple pairs of protein-protein interactions (PPIs) with other proteins, and these PPIs have an effect on the regulation of autophagosome formation and the recruitment of autophagic substrates. In our previous work, a small molecule covalent inhibitor DC-LC3in-D5 which could inhibit LC3A/B PPIs was identified, but a detailed study of structure-activity relationships (SARs) was lacking. Herein, a new molecule LC3in-C42 was discovered utilizing the hybridization of advantageous fragments, whose potency (IC50 = 7.6 nM) had been greatly improved compared with that of DC-LC3in-D5. LC3in-C42 inhibits autophagy at the cellular level and its efficacy far exceeds that of DC-LC3in-D5. Thus far, LC3in-C42 stands as the most potent LC3A/B small molecule inhibitor. LC3in-C42 could serve as a powerful tool for LC3A/B protein and autophagy research.
WOS关键词DRUG DISCOVERY ; AUTOPHAGY ; LIPIDATION ; ATG8 ; CONJUGATE ; INDOLES ; FAMILY ; TARGET ; MOTIF
资助项目National Key R&D Program of China[2022YFC3400500] ; National Key R&D Program of China[2021ZD0203900] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[92253303] ; National Natural Science Foundation of China[U23A20108] ; National Natural Science Foundation of China[82341017] ; National Natural Science Foundation of China[22337004] ; National Natural Science Foundation of China[82273853] ; National Natural Science Foundation of China[2240070082] ; National Administration of Traditional Chinese Medicine[ZYYCXTD-202004] ; Science and Technology Commission of Shanghai Municipality[YDZX20233100004032] ; Shandong Laboratory Program[SYS202205]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001270075300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312383]  
专题中国科学院上海药物研究所
通讯作者Chen, Kaixian; Fu, Wei; Luo, Cheng
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550014, Peoples R China
3.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangdong 528400, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
8.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Zhenfei,Huang, Siqi,Fan, Shijie,et al. Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(14):12184-12204.
APA Zhou, Zhenfei.,Huang, Siqi.,Fan, Shijie.,Li, Xueyuan.,Wang, Chengyu.,...&Luo, Cheng.(2024).Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor.JOURNAL OF MEDICINAL CHEMISTRY,67(14),12184-12204.
MLA Zhou, Zhenfei,et al."Structure-Based Design and Discovery of a Potent and Cell-Active LC3A/B Covalent Inhibitor".JOURNAL OF MEDICINAL CHEMISTRY 67.14(2024):12184-12204.

入库方式： OAI收割

来源：上海药物研究所

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