Discovery of Covalent and Cell-Active ALKBH5 Inhibitors with Potent Antileukemia Effects In Vivo
文献类型：期刊论文
| 作者 | Wu, Hengbo3,5; Lai, Gan-Qiang3,5; Cheng, Ruixiang3,5; Huang, Hui5; Wang, Ju3,4,5; Liu, Zeyu2,5; Gao, Jing5; Zhou, Hu3,4,5 ; Li, Chunpu3,4,5; Yang, Cai-Guang1,3,4,5
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| 刊名 | ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
 |
| 出版日期 | 2025-03-02 |
| 页码 | 9 |
| 关键词 | RNA epigenetics
|
| DOI | 10.1002/anie.202424928 |
| 英文摘要 | The N6-methyladenosine (m6A) demethylase ALKBH5 is the only other identified m6A eraser except for FTO, and dysregulated ALKBH5 functions were closely associated with leukemogenesis. However, the development of ALKBH5 inhibitors is slow compared to FTO inhibitors. Inspired by a non-catalytic C200-covalent strategy, a series of maleimide derivatives were designed and synthesized as potent and covalent ALKBH5 inhibitors in this work. The analog 18 l exhibited excellent inhibitory effects on ALKBH5 (IC50=0.62 mu M), and exerted a strong antiproliferative effect on NB4 cells with IC50 of 0.63 mu M. The Kd value of 18 l binding to ALKBH5 was 804 nM, while no binding was observed with FTO. This result indicated that 18 l was a highly selective inhibitor of ALKBH5 rather than FTO. Additionally, proteomic experiments showed that 18 l directly targeted ALKBH5 in cells and altered m6A levels on mRNA, blocked the related downstream signal pathways, promoted differentiation, and induced apoptosis. Furthermore, 18 l exerted excellent in vivo antitumor activity with TGITV values of 66.3 % at 1 mg/kg in NB4 tumor xenograft models. |
| WOS关键词 | GENE-EXPRESSION ; RNA MODIFICATIONS ; DEMETHYLASE ; METABOLISM |
| 资助项目 | the National Key R&D Program of China[2023YFF1205104] ; the National Key R&D Program of China[2022YFC2705005] ; National Key R&D Program of China[82273766] ; National Key R&D Program of China[82130105] ; National Key R&D Program of China[92153303] ; National Natural Science Foundation of China[2020282] ; Youth Innovation Promotion Association CAS |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001434977300001 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316481]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Li, Chunpu; Yang, Cai-Guang; Liu, Hong |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 2.Tsinghua Univ, Sch Pharmaceut Sci, Beijing 100084, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Hengbo,Lai, Gan-Qiang,Cheng, Ruixiang,et al. Discovery of Covalent and Cell-Active ALKBH5 Inhibitors with Potent Antileukemia Effects In Vivo[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2025:9. |
| APA | Wu, Hengbo.,Lai, Gan-Qiang.,Cheng, Ruixiang.,Huang, Hui.,Wang, Ju.,...&Liu, Hong.(2025).Discovery of Covalent and Cell-Active ALKBH5 Inhibitors with Potent Antileukemia Effects In Vivo.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,9. |
| MLA | Wu, Hengbo,et al."Discovery of Covalent and Cell-Active ALKBH5 Inhibitors with Potent Antileukemia Effects In Vivo".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (2025):9. |
入库方式： OAI收割
来源：上海药物研究所
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