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Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms

文献类型：期刊论文

作者Hu, Linghao4,6; Xu, Hesong3,5; Xu, Ye3,5; Chen, Haowen2; Jiang, Hanrui6; Xu, Dounan6; Zhang, Huimin3; Luo, Cheng3,5,6; Chen, Shijie1,3; Wang, Mingliang2,4,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-02-05
卷号283页码:17
关键词NSD2 RE-IIBP Targeted protein degradation Multiple myeloma
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.117179
通讯作者Chen, Shijie(sjchen@pharm.ecnu.edu.cn) ; Wang, Mingliang(wangmingliang@simm.ac.cn)
英文摘要Nuclear receptor binding SET domain protein 2 (NSD2) is involved in various pathologic processes and is considered as an important target for cancer therapy. Due to alternative splicing, NSD2 has 3 isoforms: long, short and RE-IIBP. Although previous studies reported the degradation of PWWP1 domain-containing NSD2-long and short isoforms through PWWP1-binding molecules, the degradation of RE-IIBP which does not contain PWWP1 has been neglected to date. However, RE-IIBP plays an important role in cancer pathology, the further investigation of RE-IIBP requires novel chemical tools. Therefore, 31 novel SET domain ligand-based compounds bearing different E3 ligase ligands and amine moieties were synthesized and evaluated in this work. For the first time, the simultaneous degradation of NSD2-long and RE-IIBP isoforms was achieved through the primary alkylamine degrader ND-L11B. The degradation induced by ND-L11B led to the reduction of H3K36me2 level. Moreover, compared to the corresponding SET inhibitor, ND-L11B exhibited stronger antiproliferative activity on multiple myeloma cell line and negligible effect on non-malignant normal cell line. Whereas ND-L11B induced selective multiple myeloma cytotoxicity, it could serve as a starting point for the further development of NSD2-targeting therapies. This work provided a convenient chemical knockdown tool to further elucidate the multiple functions of NSD2 isoforms and expanded the applicability of alkyl primary amine analogs for targeted protein degradation.
WOS关键词ATTRACTING CAVITIES ; NSD2 ; PROTEIN ; MMSET ; GENE ; METHYLATION
资助项目Shanghai Science and Technology Development Funds[22YF1457600] ; Guangdong Highlevel New RD Institute[2019B090904008] ; Guangdong High-level Innovative Research Institute[2021B0909050003] ; China Postdoctoral Science Foundation[2021M703348] ; Youth Innovation Promotion Association of CAS[2022279]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001394700000001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/315654]  
专题中国科学院上海药物研究所
通讯作者Chen, Shijie; Wang, Mingliang
作者单位1.East China Normal Univ, Sch Pharm, Shanghai 200241, Peoples R China
2.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Guangzhou 528400, Guangdong, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Linghao,Xu, Hesong,Xu, Ye,et al. Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,283:17.
APA Hu, Linghao.,Xu, Hesong.,Xu, Ye.,Chen, Haowen.,Jiang, Hanrui.,...&Wang, Mingliang.(2025).Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,283,17.
MLA Hu, Linghao,et al."Discovery of SET domain-binding primary alkylamine-tethered degraders for the simultaneous degradation of NSD2-long and RE-IIBP isoforms".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 283(2025):17.

入库方式： OAI收割

来源：上海药物研究所

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