Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell.
Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell.
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DOI：
10.3389/fchem.2022.888727
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发表时间：
2022
影响因子：
5.5
通讯作者：
Hong, Wei
中科院分区：
文献类型：
--
作者：
Wang, Caijiao;Dong, Luyao;Zhao, Ziqi;Zhang, Zeqing;Sun, Yutong;Li, Chonglong;Li, Guoqing;You, Xuefu;Yang, Xinyi;Wang, Hao;Hong, Wei
蛋白质精氨酸甲基转移酶1（PRMT 1）通过将S-腺苷-L-甲硫氨酸（SAM）上的甲基转移到蛋白质精氨酸的胍基氮原子上，催化蛋白质精氨酸甲基化，从而影响上皮-间质转化（EMT）和EMT介导的癌细胞迁移等多种生物学过程。PRMT 1的上调涉及多种癌症，例如肺癌，并且迫切需要开发新的和有效的PRMT 1抑制剂。本文针对PRMT 1的底物精氨酸结合位点，设计并合成了一系列2，5-取代呋喃衍生物和2，4-取代噻唑衍生物，其中10个化合物对PRMT 1具有明显的抑制作用。其中，化合物1 r（WCJ-394）的抑制作用最强，可显著影响A549细胞中PRMT 1相关蛋白的表达，下调A549细胞间质标志物的表达，从而抑制TGF-β1诱导的A549细胞EMT，阻止癌细胞迁移。目前的研究表明，WCJ-394是一种有效的PRMT 1抑制剂，可用作进一步药物发现的先导化合物。
Protein arginine methyltransferase 1 (PRMT1) can catalyze the protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes including epithelial–mesenchymal transition (EMT) and EMT-mediated mobility of cancer cells. The upregulation of PRMT1 is involved in a diverse range of cancer, such as lung cancer, and there is an urgent need to develop novel and potent PRMT1 inhibitors. In this article, a series of 2,5-substituted furan derivatives and 2,4-substituted thiazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and 10 compounds demonstrated significant inhibitory effects against PRMT1. Among them, the most potent inhibitor, compound 1r (WCJ-394), significantly affected the expression of PRMT1-related proteins in A549 cells and downregulated the expression of mesenchymal markers, by which WCJ-394 inhibited the TGF-β1-induced EMT in A549 cells and prevented the cancer cell migration. The current study demonstrated that WCJ-394 was a potent PRMT1 inhibitor, which could be used as the leading compound for further drug discovery.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
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DOI：
10.15252/embj.2020106777
发表时间：
2021-07-01
期刊：
The EMBO journal
影响因子：
--
作者：
Repenning A;Happel D;Bouchard C;Meixner M;Verel-Yilmaz Y;Raifer H;Holembowski L;Krause E;Kremmer E;Feederle R;Keber CU;Lohoff M;Slater EP;Bartsch DK;Bauer UM
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影响因子：
3.4
作者：
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影响因子：
3.5
作者：
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Bedford MT
影响因子：
4.6
作者：
Lee, Yu-Jen;Chang, Wen-Wei;Li, Chuan
通讯作者：
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