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5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma

文献类型：期刊论文

作者Wang, Shuni1,2,3; Yang, Hong1,2,3; Su, Mingbo4; Lian, Fulin1,2,3; Cong, Zhanqing1,2,3; Wei, Rongrui1,2,3; Zhou, Yubo1,2,3,5; Li, Xingjun1,2,3; Zheng, Xingling1,2,3; Li, Chunpu1,2,3,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-10-15
卷号222页码:19
ISSN号0223-5234
关键词NSD2 Methyltransferase HTS Multiple myeloma 5-Aminonaphthalene derivatives Inhibitor
DOI10.1016/j.ejmech.2021.113592
通讯作者Li, Jia(jli@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Wang, Jiang(jwang@simm.ac.cn)
英文摘要Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 mu M) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice. (C) 2021 Elsevier Masson SAS. All rights reserved.
WOS关键词HISTONE H3 ; LYSINE 36 ; MMSET ; DOXORUBICIN ; FAMILY ; GROWTH ; WHSC1 ; GENE
资助项目National Natural Science Foundation of China[21922707] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[21877118] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[91953108] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Science and Technology Commission of Shanghai Municipality[18JC1411304] ; Science and Technology Commission of Shanghai Municipality[19430750100] ; Science and Technology Commission of Shanghai Municipality[18431907100]
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:000685593800032
源URL[http://119.78.100.183/handle/2S10ELR8/298005]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Huang, Xun; Wang, Jiang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Chinese Acad Sci, Inst Drug Discovery Innovat, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
6.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Shuni,Yang, Hong,Su, Mingbo,et al. 5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,222:19.
APA Wang, Shuni.,Yang, Hong.,Su, Mingbo.,Lian, Fulin.,Cong, Zhanqing.,...&Wang, Jiang.(2021).5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,222,19.
MLA Wang, Shuni,et al."5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 222(2021):19.

入库方式： OAI收割

来源：上海药物研究所

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