Structure-Based Discovery of a Series of Novel MAT2a Inhibitors
文献类型：期刊论文
| 作者 | Zhou, Yushan1,2,3; Wang, Li4,6; Ren, Ruyue1,3,5; Zhang, Junjie1,3,4; Huan, Xiajuan6; Yang, Peng2; Miao, Ze-Hong4,6; Xiong, Bing1,3,4 ; Wang, Yingqing4,6; Liu, Tongchao1,3
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| 刊名 | ACS MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2025-03-15 |
| 页码 | 5 |
| 关键词 | MAT2a MTAP Synthetic lethality Allosteric inhibitor Structure-activity relationship |
| ISSN号 | 1948-5875 |
| DOI | 10.1021/acsmedchemlett.5c00049 |
| 英文摘要 | Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC50 = 20 nM) and significantly enhanced antiproliferative activity (IC50 = 10 nM against HAP1MTAP-/- cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270. |
| WOS关键词 | S-ADENOSYLMETHIONINE ; DESIGN |
| 资助项目 | National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[81773572] ; National Natural Science Foundation of China[82204187] ; National Natural Science Foundation of China[XDB1060402] ; Strategic Priority Research Program of the Chinese Academy of Sciences |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001445727000001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316644]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xiong, Bing; Wang, Yingqing; Liu, Tongchao |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 2.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Liaoning, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Shanxi Med Univ, Sch Pharm, Taiyuan 030001, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Yushan,Wang, Li,Ren, Ruyue,et al. Structure-Based Discovery of a Series of Novel MAT2a Inhibitors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2025:5. |
| APA | Zhou, Yushan.,Wang, Li.,Ren, Ruyue.,Zhang, Junjie.,Huan, Xiajuan.,...&Liu, Tongchao.(2025).Structure-Based Discovery of a Series of Novel MAT2a Inhibitors.ACS MEDICINAL CHEMISTRY LETTERS,5. |
| MLA | Zhou, Yushan,et al."Structure-Based Discovery of a Series of Novel MAT2a Inhibitors".ACS MEDICINAL CHEMISTRY LETTERS (2025):5. |
入库方式： OAI收割
来源：上海药物研究所
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