Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783256944993107968 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5555576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT kongguimei selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT yumin selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT guzhongping selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT chenzhi selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT xuruiming selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT obryantdeon selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity AT wangzhengxin selectivesmallchemicalinhibitorsofproteinargininemethyltransferase5withantilungcanceractivity |