Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy
文献类型：期刊论文
| 作者 | Liu, Lu4,5; Qiu, Yuanlai3,5; Suo, Yuying3,4; Tong, Siyao3,5; Wang, Yiqing3,5; Zhang, Xi3,5; Chen, Liang4; Huang, Yue4,5; Zhou, Huchen2; Zhou, Hu3,4,5
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| 刊名 | ACTA PHARMACEUTICA SINICA B
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| 出版日期 | 2024-12-01 |
| 卷号 | 14期号:12页码:5382-5392 |
| 关键词 | N 6-Methyladenosine FTO PROTAC RNA epigenetics Antileukemia |
| ISSN号 | 2211-3835 |
| DOI | 10.1016/j.apsb.2024.07.016 |
| 英文摘要 | The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N6-methyladenosine (m6A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitineproteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m6A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m6A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications. |
| WOS关键词 | PROTEOLYSIS-TARGETING CHIMERAS ; GENE-EXPRESSION ; PROTEIN ; SUBSTRATE ; LEUKEMIA |
| 资助项目 | National Natural Science Foundation of China[92153303] ; Research Funds of Hangzhou Institute for Advanced Study, UCAS[2023HIAS-Y026] ; National Key Research and Development Program of China[2022YFC2601800] ; Youth Innovation Promotion Association of CAS[2021277] ; Open Funding Project of State Key Laboratory of Microbial Metabolism[MMLKF22-10] ; [22077133] ; [2023HIAS-V006] ; [2020285] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001391091200001 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315588]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhou, Hu; Dong, Ze; Yang, Cai-Guang |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Pharm, State Key Lab Microbial Metab, Shanghai 200240, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.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 | Liu, Lu,Qiu, Yuanlai,Suo, Yuying,et al. Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy[J]. ACTA PHARMACEUTICA SINICA B,2024,14(12):5382-5392. |
| APA | Liu, Lu.,Qiu, Yuanlai.,Suo, Yuying.,Tong, Siyao.,Wang, Yiqing.,...&Yang, Cai-Guang.(2024).Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy.ACTA PHARMACEUTICA SINICA B,14(12),5382-5392. |
| MLA | Liu, Lu,et al."Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy".ACTA PHARMACEUTICA SINICA B 14.12(2024):5382-5392. |
入库方式： OAI收割
来源：上海药物研究所
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