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Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform

文献类型：期刊论文

作者Zhang, Yiwei2,6; Lan, Yuqiu2,6; Fan, Rufeng2,6; Feng, Lei3; Wang, Guoliang5; Wu, Xinyuan6; Wen, Lulu4; Duan, Zhiqiang6; Xia, Yueyue5; Wang, Xudong2,6
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2025-12-03
卷号147期号:48页码:44396-44405
ISSN号0002-7863
DOI10.1021/jacs.5c14634
英文摘要DNA-encoded libraries (DELs) have emerged as an effective and efficient selection strategy for lead compound discovery in academia and industry over the past few decades. Despite recent advancements in this field, DEL remains limited by sensitive DNA-based constructs, particularly with low selection success rates resulting from the random selection of targets. Here, we describe a chemoenzymatic on-DNA reaction for DEL syntheses and develop a chemoproteomic-guided DEL selection platform. This platform, termed FF tags-biocatDEL, integrates DEL technology, chemoenzymatic synthesis, and fully functionalized (FF) chemical tags to match DELs with selection targets, even with limited information about ligandable hotspots. Using two diazirine-based FF indole probes, we comprehensively surveyed binding partners in cells and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target for DEL selection. DEL01 and DEL02 were designed, synthesized, and selected against PHGDH, leading to the identification of a novel enzyme-active compound with an IC50 value of 2.5 mu M. Our strategy, utilizing FF tags-biocatDEL, establishes a generalizable workflow for rapid target hunting and ligand discovery. It provides an effective method for precisely matching DELs with potential targets, demonstrating its significant potential as a complementary approach to drug discovery based on DELs.
WOS关键词3-PHOSPHOGLYCERATE DEHYDROGENASE ; DERIVATIVES ; PATHWAY
资助项目Chinese Academy of Sciences[XDB1060000] ; Science and Technology Commission of Shanghai Municipality[21TQ016] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0220233001] ; Scientific and Innovative Action Plan of Shanghai[23HC1401200] ; National Natural Science Foundation of China[22225702] ; National Key Research and Development Program of China[2024YFA1306003]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001620791200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/322040]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Zhou, Lu; Tan, Minjia; Liao, Cangsong; Lu, Xiaojie
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
4.Tianjin Univ Tradit Chinese Med, Tianjin 301617, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.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		 Zhang, Yiwei,Lan, Yuqiu,Fan, Rufeng,et al. Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(48):44396-44405.
APA Zhang, Yiwei.,Lan, Yuqiu.,Fan, Rufeng.,Feng, Lei.,Wang, Guoliang.,...&Lu, Xiaojie.(2025).Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(48),44396-44405.
MLA Zhang, Yiwei,et al."Biocatalytic- and Chemoproteomic-Guided Discovery of a PHGDH Inhibitor from Chemoenzymatic-Promoted DNA-Encoded Libraries Selection Platform".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.48(2025):44396-44405.

入库方式： OAI收割

来源：上海药物研究所

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