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Discovery of a PROTAC degrader for METTL3-METTL14 complex

文献类型：期刊论文

作者Du, Wenhao6,9; Huang, Yuting8; Chen, Xiaoai6,9; Deng, Yue5,7; Sun, Yaoliang9; Yang, Hong7,8; Shi, Qiongyu8; Wu, Feifei5,9; Liu, Guobin6; Huang, He1,2,6
刊名CELL CHEMICAL BIOLOGY
出版日期2024-01-18
卷号31期号:1页码:25
ISSN号2451-9456
DOI10.1016/j.chembiol.2023.12.009
通讯作者Huang, Xun(xhuang@lglab.ac.cn) ; Xu, Shilin(slxu@simm.ac.cn)
英文摘要N6-methyladenosine (m6A) methylation is the most abundant type of RNA modification that is mainly catalyzed by the METTL3-METTL14 methyltransferase complex. This complex has been linked to multiple cancers and is considered a promising therapeutic target for acute myeloid leukemia (AML). However, only a few METTL3 inhibitors targeting the catalytic activity were developed recently. Here, we present the discovery of WD6305 as the potent and selective proteolysis -targeting chimera (PROTAC) degrader of METTL3METTL14 complex. WD6305 suppresses m6A modification and the proliferation of AML cells, and promotes apoptosis much more effectively than its parent inhibitor. WD6305 also affects a variety of signaling pathways related to the development and proliferation of AML. Collectively, our study reveals PROTAC degradation of METTL3-METTL14 complex as a potential anti -leukemic strategy and provides desirable chemical tool for further understanding METTL3-METTL14 protein functions.
WOS关键词RNA ; DIFFERENTIATION ; TRANSLATION ; METHYLATION ; LEUKEMIA
资助项目Shanghai Subject Chief Scientist[22XD1425300] ; Collaborative Inno-vation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Open Program of State Key Laboratory of new Drug development[SIMM2105KF-04] ; SA-SIBS Scholarship Program, China Postdoctoral Science Foundation[2021M703353] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:001176030000001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/310372]  
专题新药研究国家重点实验室
通讯作者Huang, Xun; 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, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
7.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
8.Lingang Lab, Shanghai 200031, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Du, Wenhao,Huang, Yuting,Chen, Xiaoai,et al. Discovery of a PROTAC degrader for METTL3-METTL14 complex[J]. CELL CHEMICAL BIOLOGY,2024,31(1):25.
APA Du, Wenhao.,Huang, Yuting.,Chen, Xiaoai.,Deng, Yue.,Sun, Yaoliang.,...&Xu, Shilin.(2024).Discovery of a PROTAC degrader for METTL3-METTL14 complex.CELL CHEMICAL BIOLOGY,31(1),25.
MLA Du, Wenhao,et al."Discovery of a PROTAC degrader for METTL3-METTL14 complex".CELL CHEMICAL BIOLOGY 31.1(2024):25.

入库方式： OAI收割

来源：上海药物研究所

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