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Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase

文献类型：期刊论文

作者Sun, Yaoliang7; Zhang, Ying5,6; Chen, Xiaoai4; Yu, Aisong5,6; Du, Wenhao4; Huang, Yuting5,6; Wu, Feifei5,7; Yu, Lei3; Li, Jiayi2; Wen, Cuiyun7
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-09-05
卷号239页码:18
ISSN号0223-5234
关键词NSD3 PROTAC Degrader Methyltransferase
DOI10.1016/j.ejmech.2022.114528
通讯作者Geng, Meiyu(mygeng@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要Nuclear receptor binding SET domain protein 3 (NSD3) is an attractive potential target in the therapy for human cancers. Herein, we report the discovery of a series of small-molecule NSD3 degraders based on the proteolysis targeting chimera (PROTAC) strategy. The represented compound 8 induces NSD3 degradation with DC50 values of 1.43 and 0.94 mu M in NCI-H1703 and A549 lung cancer cells, respectively, and shows selectivity over two other NSD proteins. 8 reduces histone H3 lysine 36 methylation and induces apoptosis and cell cycle arrest in lung cancer cells. Moreover, the RNA sequencing and immunohistochemistry assays showed that 8 downregulates NSD3-associated gene expression. Significantly, 8 , but not 1 (a reported NSD3-PWWP antagonist) could inhibit the cell growth of NCI-H1703 and A549 cells. A single administration of 8 effectively decreases the NSD3 protein level in lung cancer xenograft models. Therefore, this study demonstrated that inducing NSD3 degradation is a more effective approach inhibiting the function of NSD3 than blocking the NSD3-PWWP domain, which may provide a potential therapeutic approach for lung cancer.
资助项目Natural Science Foundation of Shanghai (China)[21ZR1475500] ; Young Elite Scientists Sponsorship Program by CAST (China)[2019-2021QNRC001] ; Open Program of State Key Laboratory of Drug Research (China)[SIMM2105KF-04] ; China Postdoctoral Science Foundation[2021M703353] ; Shanghai Sailing Program[22YF1457500] ; National Natural Science Foundation of China[8210130546] ; National Natural Science Foundation of China[21922707] ; General Program of National Natural Science Foundation of China[82173835] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (China)[2019CXJQ02] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project
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:000833534600006
源URL[http://119.78.100.183/handle/2S10ELR8/301887]  
专题新药研究国家重点实验室
通讯作者Geng, Meiyu; Huang, Xun; Xu, Shilin
作者单位1.Lingang Lab, Shanghai 200210, Peoples R China
2.UCAS, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Tongji Univ, Tongji Univ Canc Ctr, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200092, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 ZuChongZhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Yaoliang,Zhang, Ying,Chen, Xiaoai,et al. Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,239:18.
APA Sun, Yaoliang.,Zhang, Ying.,Chen, Xiaoai.,Yu, Aisong.,Du, Wenhao.,...&Xu, Shilin.(2022).Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,239,18.
MLA Sun, Yaoliang,et al."Discovery of a potent and selective proteolysis targeting chimera (PROTAC) degrader of NSD3 histone methyltransferase".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 239(2022):18.

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来源：上海药物研究所

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