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Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function

文献类型：期刊论文

作者Jin, Yuheng9; Qi, Xuxin1,8; Yu, Xiaoli9; Cheng, Xirui1,8; Chen, Boya1,8; Wu, Mingfei9; Zhang, Jingyu9; Yin, Hao1,8; Lu, Yang9; Zhou, Yihui1,8
刊名ACTA PHARMACEUTICA SINICA B
出版日期2025-03-01
卷号15期号:3页码:1659-1679
关键词HDAC7 PROTAC Selectivity Hematologic malignancies Non-enzymatic function
ISSN号2211-3835
DOI10.1016/j.apsb.2025.01.021
通讯作者Che, Jinxin(chejx@zju.edu.cn) ; Cao, Ji(caoji88@zju.edu.cn) ; He, Qiaojun(qiaojunhe@zju.edu.cn) ; Dong, Xiaowu(dongxw@zju.edu.cn)
英文摘要HDAC7, a member of class IIa HDACs, plays a pivotal regulatory role in tumor, immune, fibrosis, and angiogenesis, rendering it a potential therapeutic target. Nevertheless, due to the high similarity in the enzyme active sites of class IIa HDACs, inhibitors encounter challenges in discerning differences among them. Furthermore, the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes, leading to a limited impact of enzymatic inhibitors on their function. In this study, proteolysis targeting chimera (PROTAC) technology was employed to develop HDAC7 drugs. We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma (DLBCL) and acute myeloid leukemia (AML) cells. Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7, thereby exerting proliferative inhibition in DLBCL. Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies, particularly in DLBCL and AML. 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词II HISTONE DEACETYLASES ; INHIBITION ; INSIGHTS ; REVEALS
资助项目National Natural Science Foundation of China[82173660] ; National Natural Science Foundation of China[82103975] ; Zhejiang Provincial Key Research & Development Plan[2023C03111] ; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province[LR21H300003] ; Natural Science Fund for Distinguished Young Scholars of Zhejiang Province[LR22H310002] ; Natural Science Foundation of Zhejiang Province[LQ21H300005]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001464734100001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317437]  
专题中国科学院上海药物研究所
通讯作者Che, Jinxin; Cao, Ji; He, Qiaojun; Dong, Xiaowu
作者单位1.Zhejiang Univ, Canc Ctr, Hangzhou 310058, Peoples R China
2.Zhejiang Univ, Hangzhou Inst Innovat Med, Hangzhou 310058, Peoples R China
3.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China
4.Minist Educ, Engn Res Ctr Innovat Anticanc Drugs, Hangzhou 310000, Peoples R China
5.Minist Educ, Ctr Med Res & Innovat Digest Syst Tumors, Hangzhou 310020, Peoples R China
6.Macao Polytech Univ, Fac Appl Sci, Ctr Artificial Intelligence Driven Drug Discovery, Macau 999078, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
8.Zhejiang Univ, Inst Pharmacol & Toxicol, Zhejiang Prov Key Lab Anticanc Drug Res, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
9.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China
推荐引用方式
GB/T 7714		 Jin, Yuheng,Qi, Xuxin,Yu, Xiaoli,et al. Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function[J]. ACTA PHARMACEUTICA SINICA B,2025,15(3):1659-1679.
APA Jin, Yuheng.,Qi, Xuxin.,Yu, Xiaoli.,Cheng, Xirui.,Chen, Boya.,...&Dong, Xiaowu.(2025).Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function.ACTA PHARMACEUTICA SINICA B,15(3),1659-1679.
MLA Jin, Yuheng,et al."Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function".ACTA PHARMACEUTICA SINICA B 15.3(2025):1659-1679.

入库方式： OAI收割

来源：上海药物研究所

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