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Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors

文献类型：期刊论文

作者Duan, Haiting9; Zhang, Jingyu7,8,9; Gui, Renzhao5,6; Lu, Yang9; Pang, Ao9; Chen, Beijing6; Shen, Liteng9; Yu, Hengyuan; Li, Jia3,4,5,6; Xu, Tengfei
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-06-24
页码28
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c00883
通讯作者Dong, Xiaowu(dongxw@zju.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Che, Jinxin(chejx@zju.edu.cn)
英文摘要BRD9 is a pivotal epigenetic factor involved in cancers and inflammatory diseases. Still, the limited selectivity and poor phenotypic activity of targeted agents make it an atypically undruggable target. PROTAC offers an alternative strategy for overcoming the issue. In this study, we explored diverse E3 ligase ligands for the contribution of BRD9 PROTAC degradation. Through molecular docking, binding affinity analysis, and structure-activity relationship study, we identified a highly potent PROTAC E5, with excellent BRD9 degradation (DC50 = 16 pM) and antiproliferation in MV4-11 cells (IC50 = 0.27 nM) and OCI-LY10 cells (IC50 = 1.04 nM). E5 can selectively degrade BRD9 and induce cell cycle arrest and apoptosis. Moreover, the therapeutic efficacy of E5 was confirmed in xenograft tumor models, accompanied by further RNA-seq analysis. Therefore, these results may pave the way and provide the reference for the discovery and investigation of highly effective PROTAC degraders.
资助项目Guangdong Provincial Introduction of Innovative Research and Development Team[82173660] ; Guangdong Provincial Introduction of Innovative Research and Development Team[82103975] ; National Natural Science Foundation of China[2023000003] ; National Natural Science Foundation of China[2019B090904008] ; Guangdong High-level new RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[2021C03083] ; Guangdong High-level Innovative Research Institute[2023C03111] ; Zhejiang Provincial Key Research & Development Plan[LR21H300003] ; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province[LHDMD22H300001] ; Huadong Medicine-Joint Funds of the Zhejiang Provincial Natural Science Foundation of China[2022C03155] ; Huadong Medicine-Joint Funds of the Zhejiang Provincial Natural Science Foundation of China[2023C03112] ; Key Project of Science and Technology Commission of Zhejiang Province[tstp0648] ; Taishan Scholars Program
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001253343300001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/311938]  
专题新药研究国家重点实验室
通讯作者Dong, Xiaowu; Zhou, Yubo; Che, Jinxin
作者单位1.Macao Polytech Univ, Fac Appl Sci, Ctr Artificial Intelligence Driven Drug Discovery, Macau 999078, Peoples R China
2.Shaanxi Univ Chinese Med, Coll Pharm, Xianyang 712046, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
4.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
7.Hangzhou Geriatr Hosp, Dept Clin Pharmacol, Hangzhou 310022, Zhejiang, Peoples R China
8.Zhejiang Univ, Hangzhou Peoples Hosp 1, Canc Ctr, Key Lab Clin Canc Pharmacol & Toxicol Res Zhejiang, R China, Hangzhou 310006, Peoples R China
9.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Duan, Haiting,Zhang, Jingyu,Gui, Renzhao,et al. Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:28.
APA Duan, Haiting.,Zhang, Jingyu.,Gui, Renzhao.,Lu, Yang.,Pang, Ao.,...&Che, Jinxin.(2024).Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors.JOURNAL OF MEDICINAL CHEMISTRY,28.
MLA Duan, Haiting,et al."Discovery of a Highly Potent and Selective BRD9 PROTAC Degrader Based on E3 Binder Investigation for the Treatment of Hematological Tumors".JOURNAL OF MEDICINAL CHEMISTRY (2024):28.

入库方式： OAI收割

来源：上海药物研究所

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