化学
蛋白质精氨酸甲基转移酶5
前药
核苷
磺胺
对接(动物)
结构-活动关系
脚手架
可药性
IC50型
生物化学
立体化学
体外
甲基化
甲基转移酶
DNA
医学
护理部
生物医学工程
基因
作者
Yuting Chen,Qiongyu Shi,Hong Yang,Jiayi Li,Kaixin Zhou,Junjie Zhang,Zekun Wang,Shi Huan-yu,Bing Xiong,Jia Liu,Xun Huang,Tongchao Liu
标识
DOI:10.1016/j.bioorg.2022.106228
摘要
Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC50 value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell-based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and suppressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold.
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