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Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach

文献类型：期刊论文

作者Qin, Shaozhao2,3; Feng, Lijian1; Zhao, Qingyi2,3; Yan, Ziqin3; Lyu, Xilin3; Li, Kaige2,3; Mu, Baiyang3; Chen, Yujie3,4; Lu, Weiwei3; Wang, Chao3,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-03
卷号67期号:2页码:1079-1092
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01463
通讯作者Zhao, Yujun(yjzhao@simm.ac.cn) ; Duan, Zhiqiang(duanzq@simm.ac.cn) ; Zhu, Jidong(zhujidong@eternbio.com) ; Lu, Xiaojie(xjlu@simm.ac.cn)
英文摘要The DNA-encoded library (DEL) is a powerful hit generation tool for chemical biology and drug discovery; however, the optimization of DEL hits remained a daunting challenge for the medicinal chemistry community. In this study, hit compounds targeting the WIN binding domain of WDR5 were discovered by the initial three-cycle linear DEL selection, and their potency was further enhanced by a cascade DEL selection from the focused DEL designed based on the original first run DEL hits. As expected, these new compounds from the second run of focused DEL were more potent WDR5 inhibitors in the protein binding assay confirmed by the off-DNA synthesis. Interestingly, selected inhibitors exhibited good antiproliferative activity in two human acute leukemia cell lines. Taken together, this new cascade DEL selection strategy may have tremendous potential for finding high-affinity leads against WDR5 and provide opportunities to explore and optimize inhibitors for other targets.
WOS关键词POTENT
资助项目Science and Technology Commission of Shanghai Municipality[NSFC 91953203] ; Science and Technology Commission of Shanghai Municipality[92253305] ; Science and Technology Commission of Shanghai Municipality[21907105] ; Science and Technology Commission of Shanghai Municipality[82073682] ; National Natural Science Foundation of China[2019PJD056] ; Shanghai Pujiang Program[21ZR1475000] ; Shanghai Pujiang Program[22ZR1475000] ; Science and Technology Commission of Shanghai Municipality ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001151502500001
源URL[http://119.78.100.183/handle/2S10ELR8/308939]  
专题新药研究国家重点实验室
通讯作者Zhao, Yujun; Duan, Zhiqiang; Zhu, Jidong; Lu, Xiaojie
作者单位1.Etern Biopharm Shanghai Co Ltd, Shanghai 201203, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Qin, Shaozhao,Feng, Lijian,Zhao, Qingyi,et al. Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(2):1079-1092.
APA Qin, Shaozhao.,Feng, Lijian.,Zhao, Qingyi.,Yan, Ziqin.,Lyu, Xilin.,...&Lu, Xiaojie.(2024).Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach.JOURNAL OF MEDICINAL CHEMISTRY,67(2),1079-1092.
MLA Qin, Shaozhao,et al."Discovery and Optimization of WDR5 Inhibitors via Cascade Deoxyribonucleic Acid-Encoded Library Selection Approach".JOURNAL OF MEDICINAL CHEMISTRY 67.2(2024):1079-1092.

入库方式： OAI收割

来源：上海药物研究所

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