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Design, synthesis, and biological evaluation of a bioavailable EZH2 PROTAC with a 2,8-diazaspiro[4.5]decane linker

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资源类型：
Pubmed体系：
作者：
Wei Wei[2] * ; Yang Tianqiong[3] * ; Zhao Ziqiao[1] * ; Huang Kun[1] ; Tao Longyue[3] ; Luo Shuang[1] ; Liu Jie[1] ; Deng Yuanle[1] ; Shi Lihong[1] ; Wang Ting[2] ; Liu Zhihao[3] ; Yu Luoting[3] ; Zhu Yongxia[1] ;
机构： [1]Department of Pharmacy, Precision Radiation in Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610041, China [2]Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610041, China [3]Department of Emergency Medicine and Laboratory of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
出处：
DOI： 10.1016/j.bioorg.2025.109223
ISSN：

关键词： EZH2 PROTAC Structure–activity relationship Non-catalytic function AML

摘要：
Enhancer of zeste homolog 2 (EZH2) serves as a oncoprotein through catalyzing the methylation of substrates dependent on PRC2 complex, or driving gene transcription independent on enzymatic activities. Given that EZH2 is an important therapeutic target for cancer, protein degradation is an effective strategy to completely suppress its catalytic and non-catalytic functions. Herein, we designed a new class of CRBN-based EZH2 PROTACs by taking advantage of rigid linkers. Structure-activity relationship study identified compound 5g as an EZH2 PROTAC that degraded target protein and subunits of PRC2 complex in different cancer cell lines, with inhibition of H3K27me3, while it was selective over GSPT1 and IKZF1/3. Additionally, the degradation effect of 5g was dependent on the ubiquitin-proteasome system. Moreover, 5g showed antiproliferative activities against different cancer cell lines, while acute myeloid leukemia (AML) cells were more sensitive. In MV4-11 cells, 5g altered genes related to cell cycle and apoptosis in transcriptomic analysis, which was consistent with the G0/G1 phase arrest, increased cell apoptosis and changes in mRNA levels of downstream target genes after treatment with 5g. Furthermore, 5g exhibited acceptable predicted ADMET properties and had an oral bioavailability of 8.91 %. These findings indicated that compound 5g was a promising starting point for the further development of EZH2 PROTACs to treat AML.Copyright © 2025 Elsevier Inc. All rights reserved.

基金：
the National Natural Science Foundation of China (grant number: 82304454 and 22377086), the Tianfu Jincheng Laboratory, City of Future Medicine (grant number: TFJC-2024-JB001),the Excellent Youth Fund of Sichuan Cancer Hospital (grant number:YB2023023), and the Sichuan Science and Technology Program (grant number: 2024NSFSC1742).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类 | 2 区 医学
小类 | 1 区 有机化学 2 区 生化与分子生物学
最新[2025]版：
大类 | 2 区 医学
小类 | 1 区 有机化学 2 区 生化与分子生物学
第一作者：
第一作者机构： [2]Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610041, China
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Wei Wei,Yang Tianqiong,Zhao Ziqiao,et al.Design, synthesis, and biological evaluation of a bioavailable EZH2 PROTAC with a 2,8-diazaspiro[4.5]decane linker[J].Bioorganic Chemistry.2025,167:109223.doi:10.1016/j.bioorg.2025.109223.
APA：
Wei Wei,Yang Tianqiong,Zhao Ziqiao,Huang Kun,Tao Longyue...&Zhu Yongxia.(2025).Design, synthesis, and biological evaluation of a bioavailable EZH2 PROTAC with a 2,8-diazaspiro[4.5]decane linker.Bioorganic Chemistry,167,
MLA：
Wei Wei,et al."Design, synthesis, and biological evaluation of a bioavailable EZH2 PROTAC with a 2,8-diazaspiro[4.5]decane linker".Bioorganic Chemistry 167.(2025):109223

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