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Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma

文献类型：期刊论文

作者Jin, Yuheng10; Liao, Xueyan6,9; Zhang, Jingyu10; Duan, Haiting10; Xu, Ran8; Luo, Xiaomin9; Yu, Xiaoli10; Li, Bizhi10; Wang, Jia1; Li, Xian9
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-10-23
卷号68期号:20页码:21249-21281
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c01159
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn) ; Che, Jinxin(chejx@zju.edu.cn)
英文摘要Leveraging the synergistic effects of IMiDs-induced neo-substrate degradation with the targeted protein destruction capability of PROTACs offers a potent therapeutic strategy for combating malignancies. However, identifying synergistic targets and the corresponding PROTAC/IMiD is still a significant challenge. In this study, we present a comprehensive approach that integrates a bifunctional molecule design-oriented (BMDO) IMiD library. Taking BCL6 as a starting target, the first BCL6-PROTAC/IMiD BC6 was developed by leveraging the positive correlation between BCL6 and IKZF1/3. BC6 exhibits high selective degradation activity of BCL6 and IKZF1/3, demonstrating superior antiproliferative effects in various germinal center B-cell-like (GCB) and activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cell lines and significant in vivo antitumor efficacy. The process also facilitates the discovery of a novel BTK-PROTAC/IMiD BT6. These results pave the way for a promising new treatment avenue for DLBCL, with broad implications for the design of PROTAC/IMiD.
WOS关键词GERMINAL CENTER ; LENALIDOMIDE ; DEREGULATION ; GSPT1
资助项目Key Research and Development Program of Zhejiang Province[82173660] ; Key Research and Development Program of Zhejiang Province[82404402] ; National Natural Science Foundation of China[2023C03111] ; Zhejiang Provincial Key Research & Development Plan[2023000003] ; Zhejiang Provincial Key Research & Development Plan[2019B090904008] ; 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:001593114800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321675]  
专题中国科学院上海药物研究所
通讯作者Zhou, Yubo; Dong, Xiaowu; Che, Jinxin
作者单位1.Sichuan Agr Univ, Coll Sci, Yaan 625104, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Stake Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Hangzhou Med Coll, Key Lab Neuropsychiat Drug Res Zhejiang Prov, Hangzhou 310013, Peoples R China
4.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
5.Zhejiang Univ, Coll Pharmaceut Sci, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China
6.Zunyi Med Univ, Sch Pharm, Zunyi 563006, Peoples R China
7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
8.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
9.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
10.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Jin, Yuheng,Liao, Xueyan,Zhang, Jingyu,et al. Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(20):21249-21281.
APA Jin, Yuheng.,Liao, Xueyan.,Zhang, Jingyu.,Duan, Haiting.,Xu, Ran.,...&Che, Jinxin.(2025).Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma.JOURNAL OF MEDICINAL CHEMISTRY,68(20),21249-21281.
MLA Jin, Yuheng,et al."Modular PROTAC/IMiD Bifunctional Molecule Design for the Degradation of Synergistic Targets in the Treatment of Lymphoma".JOURNAL OF MEDICINAL CHEMISTRY 68.20(2025):21249-21281.

入库方式： OAI收割

来源：上海药物研究所

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