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Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia

文献类型：期刊论文

作者Zou, Wanyi5,6; Li, Mengna4,6; Wan, Shili6; Ma, Jingkun5,6; Lian, Linan4,6; Luo, Guanghao5,6; Zhou, Yubo3,4,5,6; Li, Jia1,2,3,4,5,6; Zhou, Bing1,2,4,5,6
刊名ADVANCED SCIENCE
出版日期2024-08-09
页码8
关键词acute leukemia MDM2 oxidative phosphorylation PRMT3 PROTAC
DOI10.1002/advs.202405963
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要Protein arginine methyltransferase 3 (PRMT3) plays an important role in gene regulation and a variety of cellular functions, thus, being a long sought-after therapeutic target for human cancers. Although a few PRMT3 inhibitors are developed to prevent the catalytic activity of PRMT3, there is little success in removing the cellular levels of PRMT3-deposited omega-NG,NG-asymmetric dimethylarginine (ADMA) with small molecules. Moreover, the non-enzymatic functions of PRMT3 remain required to be clarified. Here, the development of a first-in-class MDM2-based PRMT3-targeted Proteolysis Targeting Chimeras (PROTACs) 11 that selectively reduced both PRMT3 protein and ADMA is reported. Importantly, 11 inhibited acute leukemia cell growth and is more effective than PRMT3 inhibitor SGC707. Mechanism study shows that 11 induced global gene expression changes, including the activation of intrinsic apoptosis and endoplasmic reticulum stress signaling pathways, and the downregulation of E2F, MYC, oxidative phosphorylation pathways. Significantly, the combination of 11 and glycolysis inhibitor 2-DG has a notable synergistic antiproliferative effect by further reducing ATP production and inducing intrinsic apoptosis, thus further highlighting the potential therapeutic value of targeted PRMT3 degradation. These data clearly demonstrated that degrader 11 is a powerful chemical tool for investigating PRMT3 protein functions. The discovery of a first-in-class PRMT3-targeted PROTAC 11 that effectively and selectively induced PRMT3 degradation is described by recruiting MDM2 E3 ubiquitin ligase. Importantly, 11 effectively inhibited the acute leukemia cell growth and is more effective than PRMT3 inhibitor SGC707, highlighting the advantages of PRMT3 degradation over inhibition. image
WOS关键词ARGININE METHYLATION ; ALLOSTERIC INHIBITOR ; PROTEIN ; POTENT ; TARGET
资助项目National Natural Science Foundation of China[81973166] ; Science and Technology Commission of Shanghai Municipality[22XD1424600] ; Taishan Scholar Foundation of Shandong Province[tsqn202306322] ; Shandong Laboratory Program[SYS202205] ; Shandong Provincial Natural Science Foundation[ZR2023JQ028] ; Guangdong High-level new RD Institute[2023000003] ; Guangdong High-level new RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001286641500001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/312688]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Zhou, Bing
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Huizhou 528400, Guangdong, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zou, Wanyi,Li, Mengna,Wan, Shili,et al. Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia[J]. ADVANCED SCIENCE,2024:8.
APA Zou, Wanyi.,Li, Mengna.,Wan, Shili.,Ma, Jingkun.,Lian, Linan.,...&Zhou, Bing.(2024).Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia.ADVANCED SCIENCE,8.
MLA Zou, Wanyi,et al."Discovery of PRMT3 Degrader for the Treatment of Acute Leukemia".ADVANCED SCIENCE (2024):8.

入库方式： OAI收割

来源：上海药物研究所

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