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Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads

文献类型：期刊论文

作者Wu, Xinyuan6,7; Pan, Jiayi6,7; Fan, Rufeng6,7; Zhang, Yiwei6,7; Wang, Chao6,7; Wang, Guoliang1,7; Liu, Jiaxiang7; Cui, Mengqing7; Yue, Jinfeng7; Jin, Rui7
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2025-04-28
卷号147期号:18页码:15469-15481
ISSN号0002-7863
DOI10.1021/jacs.5c01712
英文摘要Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency. Covalent DNA-encoded chemical library (CoDEL) technology is an advanced platform for covalent drug discovery. However, the application of CoDELs is constrained by a single-residue focus and limited warhead diversity. Here we report a method to identify residue-selective inhibitors using CoDELs with diverse warheads targeting multiple distinct residues. We systematically evaluated the reactivity of 17 warheads with 9 nucleophilic amino acids of FGFR2 and then constructed CoDELs comprising 24.8 million compounds. These CoDELs enabled the identification of active covalent inhibitors targeting cysteine, lysine, arginine, or glutamic acid. The lysine-targeting inhibitor engaged a novel reactive site. The arginine-targeting inhibitor demonstrated subtype selectivity and overcame drug resistance. The glutamic acid-targeting inhibitor validated the druggability of this unconventional covalent residue site. These findings suggest that our work could potentially expand the target space of covalent drugs and promote precision therapy by harnessing the power of the CoDELs.
WOS关键词LUNG-CANCER ; RESISTANCE ; MUTATIONS ; ARGININE ; REAGENTS ; PATHWAY ; GENE
资助项目Innovative Research Team of High-level Local University in Shanghai[22377139] ; Innovative Research Team of High-level Local University in Shanghai[U24A20524] ; Innovative Research Team of High-level Local University in Shanghai[92253305] ; Innovative Research Team of High-level Local University in Shanghai[22225702] ; Innovative Research Team of High-level Local University in Shanghai[T2488301] ; Innovative Research Team of High-level Local University in Shanghai[81821005] ; National Natural Science Foundation of China[2024YFA1306003] ; National Key R&D Program of China[XDB0830000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[23HC1401200] ; Shanghai Action Plan for Science, Technology and Innovation[SIMM0220233001] ; Shanghai Action Plan for Science, Technology and Innovation[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SHSMU-ZDCX20212700] ; Innovative Research Team of High-Level Local Universities in Shanghai ; Shanghai Talent Program
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001478028500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/317524]  
专题新药研究国家重点实验室
通讯作者Tan, Minjia; Ai, Jing; Lu, Xiaojie
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
5.Suzhou Inst Mat Med, Suzhou 215123, Jiangsu, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wu, Xinyuan,Pan, Jiayi,Fan, Rufeng,et al. Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(18):15469-15481.
APA Wu, Xinyuan.,Pan, Jiayi.,Fan, Rufeng.,Zhang, Yiwei.,Wang, Chao.,...&Lu, Xiaojie.(2025).Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(18),15469-15481.
MLA Wu, Xinyuan,et al."Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.18(2025):15469-15481.

入库方式： OAI收割

来源：上海药物研究所

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