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Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer

文献类型：期刊论文

作者Shi, Yunkai4,5,6; Shen, Qianqian3; Long, Ruikai4,5; Mao, Yiwen4,5; Tong, Shuaihang4,5; Yang, Yaxi2,4,5,6; Gao, Jing1,4; Zhou, Hu1,4; Chen, Yi2,3,4; Zhou, Bing2,4,5,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-07-23
卷号67期号:15页码:13271-13285
ISSN号0022-2623
DOI10.1021/acs.jmedchem.4c01192
通讯作者Chen, Yi(ychen@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要G9a, which was initially identified as a histone H3 Lys9 (H3K9) methyltransferase, is potentially an attractive therapeutic target for human cancers. Despite its importance, there is no available selective G9a chemical probe because its homologous protein GLP shares approximately 80% of its sequence with G9a. The development of G9a chemical probes with high selectivity for G9a over GLP is a big challenge but is extremely valuable for understanding G9a-related biology. Herein, we developed a first-in-class selective G9a degrader G9D-4, which induced a dose- and time-dependent G9a degradation without degradation of GLP. G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRAS(G12D) mutant pancreatic cancer cells to KRAS(G12D) inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic cancer.
WOS关键词TARGETED PROTEIN-DEGRADATION ; METHYLTRANSFERASES G9A ; G9A-LIKE PROTEIN ; LYSINE METHYLTRANSFERASES ; CHEMICAL PROBE ; METHYLATION ; GLP ; EUCHROMATIN ; REPRESSION ; INHIBITORS
资助项目Science and Technology Commission of Shanghai Municipality[22XD1424600] ; Natural Science Foundation of Shanghai[22ZR1474100] ; Taishan Scholar Foundation of Shandong Province[tsqn202306322] ; Shandong Laboratory Program[SYS202205] ; Shandong Provincial Natural Science Foundation[ZR2023JQ028]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001282087100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/312700]  
专题新药研究国家重点实验室
通讯作者Chen, Yi; Zhou, Bing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Yunkai,Shen, Qianqian,Long, Ruikai,et al. Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(15):13271-13285.
APA Shi, Yunkai.,Shen, Qianqian.,Long, Ruikai.,Mao, Yiwen.,Tong, Shuaihang.,...&Zhou, Bing.(2024).Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer.JOURNAL OF MEDICINAL CHEMISTRY,67(15),13271-13285.
MLA Shi, Yunkai,et al."Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer".JOURNAL OF MEDICINAL CHEMISTRY 67.15(2024):13271-13285.

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来源：上海药物研究所

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