蛋白质精氨酸甲基转移酶5
PI3K/AKT/mTOR通路
癌症研究
癌细胞
蛋白激酶B
癌症
细胞生物学
生物
化学
信号转导
甲基转移酶
生物化学
甲基化
基因
遗传学
作者
Yingqing Chen,Mingyu Zhang,Anxin Wu,Xiaojun Yao,Qianqian Wang
出处
期刊:Molecules
[MDPI AG]
日期:2022-11-01
卷期号:27 (21): 7436-7436
标识
DOI:10.3390/molecules27217436
摘要
Protein arginine methyltransferase 5 (PRMT5) is a popular anticancer target that regulates histone or nonhistone methylation and is linked to the development and poor prognosis of non-small cell lung cancer. PRMT5 inhibitors have shown great promise in clinical trials as a cancer therapy. However, most inhibitors reported recently act in a SAM-competitive mode and lack structural diversity. In this paper, a novel non-SAM inhibitor, 3039-0164, was discovered by the structure-based virtual screening method. The binding mechanism of 3039-0164 to PRMT5 was revealed via molecular docking and molecular dynamics simulations. 3039-0164 inhibited PRMT5 enzymatic activity, downregulated the expression of PRMT5 downstream target genes (FGFR3 and eIF4E), and blocked the activation of the PI3K/AKT/mTOR and ERK signaling pathways. The discovery of 3039-0164 provides precise and creative hit compounds for the design optimization of PRMT5 lead compounds in non-small cell lung cancer.
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