Structure-Based Design of a Highly Potent Dual-Competitive FTO Inhibitor for Targeted m6A Demethylase Inhibition in AML
文献类型：期刊论文
| 作者 | Zhang, Xi1,2,4; Wang, Zhen1,4; Xie, Xinyun1,4; Liu, Gege1,4; Dong, Ze1,4; Yang, Cai-Guang1,2,3,4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-11-13 |
| 卷号 | 68期号:21页码:22779-22798 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c01738 |
| 英文摘要 | Fat mass and obesity-associated protein (FTO), an Fe2+/2-oxoglutarate (2-OG)-dependent RNA demethylase, removes N 6-methyladenosine (m6A) modification. FTO is overexpressed in AML, promoting pathogenesis through c-Myc upregulation. Using fragment linking of meclofenamic acid (MA) and 2-OG mimetics, we developed 8a, a substrate/2-OG dual-competitive FTO inhibitor. 8a substantially inhibits FTO demethylation, exceeding its constituent fragments' activity, with high selectivity over ALKBH3 and ALKBH5. 2-OG competition assay and docking confirm simultaneous occupation of substrate and 2-OG pockets, although the cocrystal structure revealed a different binding site. To circumvent the limitation of poor cellular permeability of 8a, we synthesized the prodrug ester 8a-1, which suppressed AML cell viability, reduced m6A levels, downregulated c-Myc and CEBPA, and upregulated ASB2 and RARA. It has also shown obvious tumor-inhibiting efficacy at the animal level. 8a represents a highly potent FTO inhibitor with therapeutic potential, providing a framework for future development. |
| WOS关键词 | MAINTENANCE |
| 资助项目 | Hangzhou Institute for Advanced Study, UCAS[2023HIAS-V006] ; National Natural Science Foundation of China[22494693] ; National Key Research and Development Program of China[2022YFC2705005] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001608520300001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/319779]  |
| 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 | Dong, Ze; Yang, Cai-Guang |
| 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, Ctr Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Xi,Wang, Zhen,Xie, Xinyun,et al. Structure-Based Design of a Highly Potent Dual-Competitive FTO Inhibitor for Targeted m6A Demethylase Inhibition in AML[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(21):22779-22798. |
| APA | Zhang, Xi,Wang, Zhen,Xie, Xinyun,Liu, Gege,Dong, Ze,&Yang, Cai-Guang.(2025).Structure-Based Design of a Highly Potent Dual-Competitive FTO Inhibitor for Targeted m6A Demethylase Inhibition in AML.JOURNAL OF MEDICINAL CHEMISTRY,68(21),22779-22798. |
| MLA | Zhang, Xi,et al."Structure-Based Design of a Highly Potent Dual-Competitive FTO Inhibitor for Targeted m6A Demethylase Inhibition in AML".JOURNAL OF MEDICINAL CHEMISTRY 68.21(2025):22779-22798. |
入库方式： OAI收割
来源：上海药物研究所
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