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Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell
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 transi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214036/ https://www.ncbi.nlm.nih.gov/pubmed/35755248 http://dx.doi.org/10.3389/fchem.2022.888727 |
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author | Wang, Caijiao Dong, Luyao Zhao, Ziqi Zhang, Zeqing Sun, Yutong Li, Chonglong Li, Guoqing You, Xuefu Yang, Xinyi Wang, Hao Hong, Wei |
author_facet | Wang, Caijiao Dong, Luyao Zhao, Ziqi Zhang, Zeqing Sun, Yutong Li, Chonglong Li, Guoqing You, Xuefu Yang, Xinyi Wang, Hao Hong, Wei |
author_sort | Wang, Caijiao |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9214036 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92140362022-06-23 Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell Wang, Caijiao Dong, Luyao Zhao, Ziqi Zhang, Zeqing Sun, Yutong Li, Chonglong Li, Guoqing You, Xuefu Yang, Xinyi Wang, Hao Hong, Wei Front Chem Chemistry 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. Frontiers Media S.A. 2022-06-08 /pmc/articles/PMC9214036/ /pubmed/35755248 http://dx.doi.org/10.3389/fchem.2022.888727 Text en Copyright © 2022 Wang, Dong, Zhao, Zhang, Sun, Li, Li, You, Yang, Wang and Hong. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Wang, Caijiao Dong, Luyao Zhao, Ziqi Zhang, Zeqing Sun, Yutong Li, Chonglong Li, Guoqing You, Xuefu Yang, Xinyi Wang, Hao Hong, Wei Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title | Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title_full | Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title_fullStr | Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title_full_unstemmed | Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title_short | Design and Synthesis of Novel PRMT1 Inhibitors and Investigation of Their Effects on the Migration of Cancer Cell |
title_sort | design and synthesis of novel prmt1 inhibitors and investigation of their effects on the migration of cancer cell |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214036/ https://www.ncbi.nlm.nih.gov/pubmed/35755248 http://dx.doi.org/10.3389/fchem.2022.888727 |
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