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ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries

文献类型：期刊论文

作者Jiang, Lulu6; Liu, Sixiu4,5; Jia, Xinglong6; Gong, Qinting6; Wen, Xin4,5; Lu, Weiwei5; Yang, Jintong6; Wu, Xinyuan4,5; Wang, Xuan5; Suo, Yanrui4,5
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2023-10-19
卷号145期号:46页码:25283-25292
ISSN号0002-7863
DOI10.1021/jacs.3c08852
通讯作者Tan, Minjia(mjtan@simm.ac.cn) ; Lu, Xiaojie(xjlu@simm.ac.cn) ; Zhou, Lu(zhoulu@fudan.edu.cn)
英文摘要DNA-encoded chemical library (DEL) has been extensively used for lead compound discovery for decades in academia and industry. Incorporating an electrophile warhead into DNA-encoded compounds recently permitted the discovery of covalent ligands that selectively react with a particular cysteine residue. However, noncysteine residues remain underexplored as modification sites of covalent DELs. Herein, we report the design and utility of tyrosine-targeting DELs of 67 million compounds. Proteome-wide reactivity analysis of tyrosine-reactive sulfonyl fluoride (SF) covalent probes suggested three enzymes (phosphoglycerate mutase 1, glutathione s-transferase 1, and dipeptidyl peptidase 3) as models of tyrosine-targetable proteins. Enrichment with SF-functionalized DELs led to the identification of a series of tyrosine-targeting covalent inhibitors of the model enzymes. In-depth mechanistic investigation revealed their novel modes of action and reactive ligand-accessible hotspots of the enzymes. Our strategy of combining activity-based proteome profiling and covalent DEL enrichment (ABPP-CoDEL), which generated selective covalent binders against a variety of target proteins, illustrates the potential use of this methodology in further covalent drug discovery.
WOS关键词IBRUTINIB ; CYSTEINE ; BINDING ; SUFEX ; BTK
资助项目Science and Technology Commission of Shanghai Municipality ; National Center for Protein Science Shanghai[22225702] ; National Center for Protein Science Shanghai[92153302] ; National Natural Science Foundation of China[22XD1420900] ; Shanghai Municipal Committee of Science and Technology[2022-94] ; International Collaborative Research Program of Institute for Chemical Research, Kyoto University ; Kyoto University On-Site Lab (Fudan-Kyoto Shanghai Lab)
WOS研究方向Chemistry
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001108450900001
源URL[http://119.78.100.183/handle/2S10ELR8/308182]  
专题新药研究国家重点实验室
通讯作者Tan, Minjia; Lu, Xiaojie; Zhou, Lu
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
2.Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Uji, Kyoto 6110011, Japan
3.Chinese Acad Sci, Shanghai Adv Res Inst, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Lulu,Liu, Sixiu,Jia, Xinglong,et al. ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2023,145(46):25283-25292.
APA Jiang, Lulu.,Liu, Sixiu.,Jia, Xinglong.,Gong, Qinting.,Wen, Xin.,...&Zhou, Lu.(2023).ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,145(46),25283-25292.
MLA Jiang, Lulu,et al."ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 145.46(2023):25283-25292.

入库方式： OAI收割

来源：上海药物研究所

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