Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein
文献类型：期刊论文
| 作者 | Wang, Huihui1,5; Wang, Zhaoliang2,4; Hu, Linghao1,3; Yang, Bingjie1,3,4; Zong, Liangyi2,4; Xu, Dounan1; Yu, Bo5; Kong, Xiangqian2,4; Wang, Mingliang1,3,4 |
| 刊名 | CHEMMEDCHEM
 |
| 出版日期 | 2024-11-07 |
| 页码 | 16 |
| 关键词 | Degrader DNMT1 DNA methylation PROTAC |
| ISSN号 | 1860-7179 |
| DOI | 10.1002/cmdc.202400467 |
| 通讯作者 | Yu, Bo(yubo@ncu.edu.cn) ; Kong, Xiangqian(kong_xiangqian@gibh.ac.cn) ; Wang, Mingliang(wangmingliang@simm.ac.cn) |
| 英文摘要 | DNA methyltransferase 1 (DNMT1) is an attractive therapeutic target for acute myelocytic leukemia (AML) and other malignancies. It has been reported that the genetic depletion of DNMT1 inhibited AML cell proliferation through reversing DNA methylation abnormalities. However, no DNMT1-targeted PROTAC degraders have been reported yet. Herein, a series of proteolysis-targeting chimera (PROTAC) degrader of DNMT1 based on dicyanopyridine scaffold and VHL E3 ubiquitin ligase ligand was developed. Among them, KW0113 (DC50=643/899 nM in MV4-11/MOLM-13 cells) exhibited optimal DNMT1 degradation. KW0113 induced DNMT1-selective degradation in a dose- and time-dependent manner through VHL engagement. Moreover, KW0113 inhibited AML cell growth by reversing promoter DNA hypermethylation and tumor-suppressor genes silencing. In conclusion, these findings proved the capability of PROTAC strategy for inducing DNMT1 degradation, demonstrated the therapeutic potential of DNMT1-targeted PROTACs. This work also provided a convenient chemical knockdown tool for DNMT1-related studies. |
| WOS关键词 | DNA METHYLTRANSFERASE 1 ; CANCER ; METHYLATION ; INHIBITORS ; GENOME ; GENES ; CELLS |
| 资助项目 | Guangdong High-level New RD Institute[2019B090904008] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[22YF1457600] ; Shanghai Science and Technology Development Funds[2021M703348] ; China Postdoctoral Science Foundation[22107101] ; National Natural Science Foundation of China[2021B1515420002] ; Guangdong Basic and Applied Basic Research Foundation[2021QN02Y734] ; Pearl River Talents Plan[SKLRD-OP-202213] ; Open Project of State Key Laboratory of Respiratory Disease[E2040340Z5] ; Guangdong Province Postdoctoral Research Workstation Funding[GIBHBRP23-03] ; Guangdong Province Postdoctoral Research Workstation Funding[GIBHBRP24-04] ; Basic Research Project of Guangzhou Institutes of Biomedicine and Health ; Analysis and Testing Center at Zhongshan Institute for Drug Discovery and Guangzhou Institutes of Biomedicine and Health |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001357459200001 |
| 出版者 | WILEY-V C H VERLAG GMBH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314503]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Yu, Bo; Kong, Xiangqian; Wang, Mingliang |
| 作者单位 | 1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangdong Prov Key Lab Stem Cell & Regenerat Med, State Key Lab Resp Dis,China New Zealand Joint Lab, Guangzhou 510530, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Nanchang Univ, Sch Chem & Chem Engn, Nanchang 330031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Huihui,Wang, Zhaoliang,Hu, Linghao,et al. Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein[J]. CHEMMEDCHEM,2024:16. |
| APA | Wang, Huihui.,Wang, Zhaoliang.,Hu, Linghao.,Yang, Bingjie.,Zong, Liangyi.,...&Wang, Mingliang.(2024).Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein.CHEMMEDCHEM,16. |
| MLA | Wang, Huihui,et al."Discovery of KW0113 as a First and Effective PROTAC Degrader of DNMT1 Protein".CHEMMEDCHEM (2024):16. |
入库方式： OAI收割
来源：上海药物研究所
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