中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 国家级研究中心
  5. 原创新药研究全国重点实验室
Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy

文献类型：期刊论文

作者Shi, Zihan2,6; Lin, Kexin3,4; Lin, Lijie4; Chen, Zhiyi3,5; Xie, Zhiyin3,6; Sun, Yaoliang2; Cui, Rongrong3; Zhang, Sulin1,3,6; Zheng, Mingyue1,3,4,5,6; Xu, Shilin1,2,4,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-11-27
卷号68期号:22页码:24213-24231
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c02062
英文摘要Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which account for approximately 15% of human tumors and currently lack effective therapies. However, existing MAT2A inhibitors often suffer from limited potency, suboptimal selectivity, and undesirable toxicity. Herein, we report a series of tricyclic furo[2,3-f]quinazolin-7(6H)-one derivatives as MAT2A inhibitors based on structure-based drug design. Among them, compound 18 (ZS34) exhibited potent MAT2A inhibitory activity (IC50 = 13.7 nM) and selectively suppressed the growth of MTAP-deficient cancer cells. Furthermore, 18 demonstrated on-target engagement in MTAP-deficient cells, as evidenced by inhibition of SAM synthesis, reduction of SDMA levels, and induction of DNA damage. Additionally, 18 displayed minimal hERG and UGT1A1 liabilities along with favorable oral pharmacokinetics. In the HCT116 MTAP-/- xenograft mouse model, the oral administration of 18 demonstrated significant antitumor efficacy without obvious toxicity. These results support 18 as a promising candidate for targeting MTAP-deficient cancers.
WOS关键词S-ADENOSYLMETHIONINE ; METHIONINE ; GROWTH ; APOPTOSIS ; DESIGN ; CELLS
资助项目Chinese Academy of Sciences[2023296] ; National Natural Science Foundation of China[22307132] ; National Key Research and Development Program of China[2023YFA1800804]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001616536200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321986]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Zhang, Sulin; Zheng, Mingyue; Xu, Shilin
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
5.Nanjing Univ, Sch Life Sci, Nanjing 210023, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Zihan,Lin, Kexin,Lin, Lijie,et al. Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(22):24213-24231.
APA Shi, Zihan.,Lin, Kexin.,Lin, Lijie.,Chen, Zhiyi.,Xie, Zhiyin.,...&Xu, Shilin.(2025).Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy.JOURNAL OF MEDICINAL CHEMISTRY,68(22),24213-24231.
MLA Shi, Zihan,et al."Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy".JOURNAL OF MEDICINAL CHEMISTRY 68.22(2025):24213-24231.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。