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Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity

Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC(50) values ranging fr...

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Autores principales: Kong, Gui-Mei, Yu, Min, Gu, Zhongping, Chen, Zhi, Xu, Rui-Ming, O'Bryant, Deon, Wang, Zhengxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555576/
https://www.ncbi.nlm.nih.gov/pubmed/28806746
http://dx.doi.org/10.1371/journal.pone.0181601
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author Kong, Gui-Mei
Yu, Min
Gu, Zhongping
Chen, Zhi
Xu, Rui-Ming
O'Bryant, Deon
Wang, Zhengxin
author_facet Kong, Gui-Mei
Yu, Min
Gu, Zhongping
Chen, Zhi
Xu, Rui-Ming
O'Bryant, Deon
Wang, Zhengxin
author_sort Kong, Gui-Mei
collection PubMed
description Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC(50) values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.
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spelling pubmed-55555762017-08-28 Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity Kong, Gui-Mei Yu, Min Gu, Zhongping Chen, Zhi Xu, Rui-Ming O'Bryant, Deon Wang, Zhengxin PLoS One Research Article Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC(50) values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development. Public Library of Science 2017-08-14 /pmc/articles/PMC5555576/ /pubmed/28806746 http://dx.doi.org/10.1371/journal.pone.0181601 Text en © 2017 Kong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kong, Gui-Mei
Yu, Min
Gu, Zhongping
Chen, Zhi
Xu, Rui-Ming
O'Bryant, Deon
Wang, Zhengxin
Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title_full Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title_fullStr Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title_full_unstemmed Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title_short Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
title_sort selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555576/
https://www.ncbi.nlm.nih.gov/pubmed/28806746
http://dx.doi.org/10.1371/journal.pone.0181601
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