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Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma

文献类型：期刊论文

作者Yu, Xiaoli8; Liao, Xueyan5,7; Zhang, Jingyu8; Wang, Hanlin4,6; Li, Xian7; Lu, Jialiang8; Zhou, Huan8; Wu, Mingfei8; Jin, Yuheng8; Zhu, Xin3,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-10-09
卷号68期号:19页码:20180-20206
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c01237
通讯作者Che, Jinxin(chejx@zju.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn)
英文摘要B-cell lymphoma 6 (BCL6) is a key transcriptional repressor implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL). However, current BCL6-targeting agents demonstrate restricted efficacy in vitro and in vivo, and the underlying mechanism remains unclear. In this study, we identified A19 as a potent BCL6 PROTAC through comprehensive structure-activity relationship (SAR) analysis. A19 induces rapid and efficient BCL6 degradation (DC50 = 34 pM in OCI-LY1 cells) and displays superior antiproliferative activity compared to the molecular glue BI3802 across multiple DLBCL cell lines. In addition, RNA-seq profiling showed that A19 and BI3802 trigger comparable changes in signaling pathways, reflecting similar transcriptomic responses. Further, oral dosing of A19 led to BCL6 degradation and inhibition of tumor growth in vivo. Overall, A19 is a valuable chemical tool and a promising lead compound toward the development of BCL6-dependent DLBCL.
WOS关键词PROTEIN ; REPRESSION ; MECHANISMS
资助项目Key Research and Development Program of Zhejiang Province[82404402] ; Key Research and Development Program of Zhejiang Province[82273951] ; National Natural Science Foundation of China[SYS202205] ; Shandong Laboratory Program[2023C03111] ; Zhejiang Provincial Key Research & Development Plan[2019B090904008] ; Zhejiang Provincial Key Research & Development Plan[2023000003] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001584729100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321588]  
专题中国科学院上海药物研究所
通讯作者Che, Jinxin; Zhou, Yubo; Dong, Xiaowu
作者单位1.Hangzhou Med Coll, Hangzhou 310053, Zhejiang, Peoples R China
2.Jiangsu Univ Technol, Inst Bioinformat & Med Engn, Sch Elect & Informat Engn, Changzhou 213001, Peoples R China
3.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Zunyi Med Univ, Sch Pharm, Zunyi 563006, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
8.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Xiaoli,Liao, Xueyan,Zhang, Jingyu,et al. Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(19):20180-20206.
APA Yu, Xiaoli.,Liao, Xueyan.,Zhang, Jingyu.,Wang, Hanlin.,Li, Xian.,...&Dong, Xiaowu.(2025).Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,68(19),20180-20206.
MLA Yu, Xiaoli,et al."Discovery of a Selective and Potent BCL6 PROTAC with Efficacious Antiproliferative Activity for the Treatment of Diffuse Large B-Cell Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 68.19(2025):20180-20206.

入库方式： OAI收割

来源：上海药物研究所

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