机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China四川大学华西医院[2]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China[3]Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China临床药学部临床药学部四川省人民医院四川省肿瘤医院
EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.
基金：
the Sichuan
Provincial Science and Technology Program for Key Research
and Development, China (No. 2018SZ0007), the Postdoctoral
Science Foundation of Sichuan University (No.
2020SCU12020), the National Natural Science Foundation
of China (No. 81702946), and the National S&T Major
Special Project on Major New Drug Innovations (No.
2018ZX09201018)
第一作者机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China[2]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China[*1]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China[*2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
推荐引用方式(GB/T 7714)：
Liu Zhihao,Hu Xi,Wang Qiwei,et al.Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.[J].JOURNAL OF MEDICINAL CHEMISTRY.2021,64(5):2829-2848.doi:10.1021/acs.jmedchem.0c02234.
APA：
Liu Zhihao,Hu Xi,Wang Qiwei,Wu Xiuli,Zhang Qiangsheng...&Yu Luoting.(2021).Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2..JOURNAL OF MEDICINAL CHEMISTRY,64,(5)
MLA：
Liu Zhihao,et al."Design and Synthesis of EZH2-Based PROTACs to Degrade the PRC2 Complex for Targeting the Noncatalytic Activity of EZH2.".JOURNAL OF MEDICINAL CHEMISTRY 64..5(2021):2829-2848
医学