Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy
文献类型：期刊论文
| 作者 | Yang, Teng7,8; Dong, Ze7,8; Du, Rong6,7,8; Wang, Yiqing6,7,8; Liu, Lu7,8; Xue, Yangyang5; Zhang, Xi4,6,7,8; Liao, Yonggang3; Gan, Jianhua2; Yu, Xiaoxuan1,5 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-06-28 |
| 卷号 | 68期号:13页码:13714-13727 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c00566 |
| 英文摘要 | N6-Methyladenosine (m6A), the most prevalent mRNA modification, undergoes dynamic regulation mediated by the demethylase fat mass and obesity-associated protein (FTO), which is aberrantly overexpressed in acute myeloid leukemia (AML) and drives leukemogenesis. Based on the structure-guided optimization of our previously reported FTO inhibitor Dac85 and fluorescein, we developed Dac590, a tricyclic benzoic acid derivative with potent FTO inhibitory activity and improved pharmacokinetic properties. Dac590 exerts a robust antiproliferative effect on AML cells by suppressing oncogenic FTO signaling. Oral administration of Dac590 significantly inhibited xenograft tumor growth and prolonged survival in AML mouse models with no observed toxicity. Notably, Dac590 synergized with decitabine to enhance DNA hypomethylation and further improve the survival rates. Our study identifies Dac590 as a potent orally bioavailable FTO inhibitor and demonstrates a combinatorial strategy through dual epigenetic modulations for enhanced AML therapy. |
| 资助项目 | National Natural Science Foundation of China[22494693] ; National Natural Science Foundation of China[22277127] ; National Natural Science Foundation of China[22077133] ; National Natural Science Foundation of China[82204443] ; National Natural Science Foundation of China[2023HIAS-Y026] ; National Natural Science Foundation of China[2023HIAS-V006] ; Research Funds of Hangzhou Institute for Advanced Study, UCAS |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001519734200001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318702]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yu, Xiaoxuan; Huang, Yue; Yang, Cai-Guang |
| 作者单位 | 1.Nanjing Univ, Sch Life Sci, State Key Lab Pharmaceut Biotechnol, Nanjing 210023, Peoples R China 2.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China 3.Rname Pharmaceut Technol Shanghai Co LTD, Shanghai 430048, Peoples R China 4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 5.Nanjing Univ Chinese Med, Jiangsu Collaborat Innovat Ctr Chinese Med Resourc, Sch Med, Nanjing 210023, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 8.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Teng,Dong, Ze,Du, Rong,et al. Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(13):13714-13727. |
| APA | Yang, Teng.,Dong, Ze.,Du, Rong.,Wang, Yiqing.,Liu, Lu.,...&Yang, Cai-Guang.(2025).Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy.JOURNAL OF MEDICINAL CHEMISTRY,68(13),13714-13727. |
| MLA | Yang, Teng,et al."Development of Orally Bioavailable FTO Inhibitors with Potent Antileukemia Efficacy".JOURNAL OF MEDICINAL CHEMISTRY 68.13(2025):13714-13727. |
入库方式： OAI收割
来源：上海药物研究所
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