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Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers

文献类型：期刊论文

作者Li, Chunzheng2; Lan, Xiaojing1,3; Li, Xinge1; Fu, Yixian1; Gui, Gang2; Li, Xiaodong2; Shen, Yanyan1; Gan, Zhenjie1; Huang, Min1,3; Zha, Xiaoming2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-01-06
卷号68期号:2页码:1222-1244
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01635
英文摘要Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal drug target in cancers bearing homozygous methylthioadenosine phosphorylase (MTAP) gene deletion. Despite the remarkable progress in the discovery and development of MAT2A inhibitors, current understanding about the selectivity of these compounds toward MTAP-deficient cancers is relatively limited. To improve the selectivity of MAT2A inhibitors for MTAP-deficient cancers remains a significant challenge. We herein reported the discovery of a series of novel MAT2A inhibitors with a 2(1H)-quinoxalinone scaffold through structure-based drug design and systematic SAR exploration. Among them, compound 28 exhibited good inhibitory activity against the enzymatic activity of MAT2A, and the significantly improved selectivity in killing MTAP-deficient cancer cells. Compound 28 also showed favorable pharmacokinetic properties and the improved in vivo anticancer activity in MTAP-deficient tumor models. These findings suggest new directions for the discovery and development of highly selective MAT2A inhibitors.
WOS关键词DESIGN
资助项目National Natural Science Foundation of China[82225046] ; National Natural Science Foundation of China[22337004] ; National Natural Science Foundation of China ; Qinglan Project of Jiangsu Province of China[YDZX20233100004032] ; Science and Technology Commission of Shanghai Municipality[2024CXPT028] ; Key R&D Program of Shandong Province
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001390591700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/315549]  
专题新药研究国家重点实验室
通讯作者Huang, Min; Zha, Xiaoming
作者单位1.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.China Pharmaceut Univ, Sch Engn, Dept Pharmaceut Engn, Nanjing 211198, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
推荐引用方式
GB/T 7714		 Li, Chunzheng,Lan, Xiaojing,Li, Xinge,et al. Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(2):1222-1244.
APA Li, Chunzheng.,Lan, Xiaojing.,Li, Xinge.,Fu, Yixian.,Gui, Gang.,...&Zha, Xiaoming.(2025).Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers.JOURNAL OF MEDICINAL CHEMISTRY,68(2),1222-1244.
MLA Li, Chunzheng,et al."Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers".JOURNAL OF MEDICINAL CHEMISTRY 68.2(2025):1222-1244.

入库方式： OAI收割

来源：上海药物研究所

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