机构：[a]Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China[b]Basic Medical Research Center, School of Medicine, Nantong University, Jiangsu, China[c]Affiliated Hospital of Chengdu University, Chengdu, Sichuan, China[d]College of Pharmacy and Biological Engineering, Chengdu University, Chengdu, China[e]School of Medicine, Chengdu University, Chengdu, China[f]Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
The inhibition of enhancer of zeste homolog 2 (EZH2) has been suggested to be synthetic lethal with polybromo-1 (PBRM1) deficiency, rendering EZH2 to be an attractive target for the treatment of PBRM1 frequently mutated cancers. In the current study, we combined computational and biochemical approaches to establish an efficient system for the screening and validation of synthetic lethal inhibitors from a large pool of chemical compounds. Five putative EZH2 inhibitors were identified through structure-based virtual screening from 47,737 chemical compounds and analyzed with molecular dynamics. The efficacy of these compounds against EZH2 was tested using PBRM1 deficient and wide-type cell lines. The compound L501-1669 selectively inhibited the proliferation of PBRM1-deficient cells and down-regulated the tri-methylation of histone H3 at Lysine 27 (H3K27me3). Importantly, we also observed an increase in apoptotic activities in L501-1669 treated PBRM1-deficient cells. Taken together, our results demonstrate that L501-1669 is a selective EZH2 inhibitor with promising application in the targeted therapy of PBRM1-deficient cancers.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|3 区生物学
小类|4 区细胞生物学
最新[2023]版：
大类|3 区生物学
小类|4 区细胞生物学
第一作者：
第一作者机构：[a]Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
共同第一作者：
通讯作者：
通讯机构：[a]Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China[e]School of Medicine, Chengdu University, Chengdu, China[f]Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
推荐引用方式(GB/T 7714)：
Kejia Huang,Rong Sun,Jiarong Chen,et al.A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells.[J].Cell cycle (Georgetown, Tex.).2020,19(7):758-771.doi:10.1080/15384101.2020.1729450.
APA：
Kejia Huang,Rong Sun,Jiarong Chen,Qianye Yang,Yucheng Wang...&Jian Li.(2020).A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells..Cell cycle (Georgetown, Tex.),19,(7)
MLA：
Kejia Huang,et al."A novel EZH2 inhibitor induces synthetic lethality and apoptosis in PBRM1-deficient cancer cells.".Cell cycle (Georgetown, Tex.) 19..7(2020):758-771
