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Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia

文献类型：期刊论文

作者Zhang, Jingyu8; Duan, Haiting8; Gui, Renzhao6,7; Wu, Mingfei8; Shen, Liteng8; Jin, Yuheng8; Pang, Ao8; Yu, Xiaoli8; Zeng, Shenxin4; Zhang, Bo3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-12-15
卷号262页码:18
ISSN号0223-5234
关键词Acute myeloid leukemia Bromodomain-containing protein 9 Proteolysis-targeting chimera Orally bioavailable Docking
DOI10.1016/j.ejmech.2023.115872
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Che, Jinxin(chejx@zju.edu.cn)
英文摘要BRD9 is essential in regulating gene transcription and chromatin remodeling, and blocking BRD9 profoundly affects the survival of AML cells. However, the inhibitors of BRD9 suffer from various drawbacks, including poor phenotype and selectivity, and BRD9 PROTACs still face the challenge of druggability, which limits the devel-opment of blocking BRD9 in AML. This study described an oral activity BRD9 PROTAC C6 by recruiting the highly efficient E3 ligase. C6 demonstrated remarkable efficacy and selectivity in BRD9 degradation with a BRD9 degradation DC50 value of 1.02 +/- 0.52 nM and no degradation of BRD4 or BRD7. Moreover, our findings highlighted its therapeutic potential, as evidenced by profound in vitro activity against the AML cell line MV4-11. Furthermore, C6 exhibited superior oral activity, with a Cmax value of 3436.95 ng/mL. These findings demonstrated that C6, as a novel BRD9 PROTAC with remarkable pharmacodynamic and pharmacokinetic properties, had the potential to be developed as a promising therapeutic agent for AML treatment.
WOS关键词TARGETING CHIMERAS PROTACS ; BRD9 ; PROGRESS ; DESIGN
资助项目National Natural Science Foundation of China[82003579] ; National Natural Science Foundation of China[82173660] ; National Natural Science Foundation of China[82103975] ; Guangdong High-level new RD Institute[2023000003] ; Guangdong High-level new RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003] ; Zhejiang Provincial Key Research & Development Plan[2021C03083] ; Zhejiang Provincial Key Research & Development Plan[2023C03111] ; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province[LR21H300003] ; Natural Science Foundation of Zhejiang Province[LQ21H300005] ; Huadong Medicine-Joint Funds of the Zhejiang Provincial Natural Science Foundation of China[LHDMD22H300001] ; Key Project of Science and Technology Commission of Zhejiang Province[2022C03155]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001102546600001
源URL[http://119.78.100.183/handle/2S10ELR8/307887]  
专题新药研究国家重点实验室
通讯作者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 712000, Peoples R China
3.Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Dept Clin Pharmacol, Key Lab Clin Canc Pharmacol & Toxicol Res Zhejiang, Hangzhou 310006, Zhejiang, Peoples R China
4.Hangzhou Med Coll, Key Lab Neuropsychiat Drug Res Zhejiang Prov, Hangzhou, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
8.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		 Zhang, Jingyu,Duan, Haiting,Gui, Renzhao,et al. Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,262:18.
APA Zhang, Jingyu.,Duan, Haiting.,Gui, Renzhao.,Wu, Mingfei.,Shen, Liteng.,...&Che, Jinxin.(2023).Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,262,18.
MLA Zhang, Jingyu,et al."Structure-based identification of new orally bioavailable BRD9-PROTACs for treating acute myelocytic leukemia".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 262(2023):18.

入库方式： OAI收割

来源：上海药物研究所

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