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Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors

文献类型：期刊论文

作者Tang, Hairong1,3; Yu, Aisong4; Xing, Li1,4; Chen, Xiaoyu1; Ding, Huaqian1,4; Yang, Hong2,4,5; Song, Zilan1; Shi, Qiongyu4; Geng, Meiyu4; Huang, Xun2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-01-15
页码18
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c01920
通讯作者Huang, Xun(xhuang@lglab.ac.cn) ; Zhang, Ao(ao6919zhang@sjtu.edu.cn)
英文摘要The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.
WOS关键词MULTIPLE-MYELOMA ; MMSET ; DIMETHYLATION ; METHYLATION
资助项目China National Innovation of Science and Technology -2030[2021ZD0204004] ; National Natural Science Foundation of China[82273767,82173835,21922707,81991523] ; Major Projects for Shanghai Zhangjiang National Independent Innovation of China[ZJ2021-ZD-007] ; Collaborative Innovation Cluster Project of Shanghai Munic- ipal Commission of Health and Family Planning[2019CXJQ02]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000920769200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/303654]  
专题新药研究国家重点实验室
通讯作者Huang, Xun; Zhang, Ao
作者单位1.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
2.Lingang Lab, Shanghai 200210, Peoples R China
3.Shanghai Jiao Tong Univ, Shanghai Key Lab Mol Engn Chiral Drugs, Shanghai 200240, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Tang, Hairong,Yu, Aisong,Xing, Li,et al. Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:18.
APA Tang, Hairong.,Yu, Aisong.,Xing, Li.,Chen, Xiaoyu.,Ding, Huaqian.,...&Zhang, Ao.(2023).Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,18.
MLA Tang, Hairong,et al."Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY (2023):18.

入库方式： OAI收割

来源：上海药物研究所

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