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Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones
Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activit...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368574/ https://www.ncbi.nlm.nih.gov/pubmed/30737440 http://dx.doi.org/10.1038/s41598-018-38217-8 |
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author | Voura, Maria Khan, Parvez Thysiadis, Savvas Katsamakas, Sotiris Queen, Aarfa Hasan, Gulam Mustafa Ali, Sher Sarli, Vasiliki Hassan, Md. Imtaiyaz |
author_facet | Voura, Maria Khan, Parvez Thysiadis, Savvas Katsamakas, Sotiris Queen, Aarfa Hasan, Gulam Mustafa Ali, Sher Sarli, Vasiliki Hassan, Md. Imtaiyaz |
author_sort | Voura, Maria |
collection | PubMed |
description | Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7d and 7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding, ITC and kinase assays. Here we used functional assays of selected potential lead molecules with commercially available panel of 26 kinases of same family. A distinctive kinase selectivity profile was observed for each compound. The selective compounds were identified with submicromolar cellular activity against MARK4. Furthermore, in vitro antitumor evaluation against cancerous cells (MCF-7 and HepG2) revealed that compounds 7b, 7d and 7f inhibit cell proliferation and predominantly induce apoptosis in MCF-7 cells, with IC(50) values of 5.2 ± 1.2 μM, 6.3 ± 1.2 μM, and 5.8 ± 1.4 μM respectively. In addition, these compounds significantly upsurge the oxidative stress in cancerous cells. Our observations support our approach for the synthesis of effective inhibitors against MARK4 that can be taken forward for the development of novel anticancer molecules targeting MARK4. |
format | Online Article Text |
id | pubmed-6368574 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63685742019-02-14 Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones Voura, Maria Khan, Parvez Thysiadis, Savvas Katsamakas, Sotiris Queen, Aarfa Hasan, Gulam Mustafa Ali, Sher Sarli, Vasiliki Hassan, Md. Imtaiyaz Sci Rep Article Microtubule affinity regulating kinase 4 (MARK4) becomes a unique anti-cancer drug target as its overexpression is responsible for different types of cancers. In quest of novel, effective MARK4 inhibitors, some acridone derivatives were synthesized, characterized and evaluated for inhibitory activity against human MARK4. Among all the synthesized compounds, three (7b, 7d and 7f) were found to have better binding affinity and enzyme inhibition activity in µM range as shown by fluorescence binding, ITC and kinase assays. Here we used functional assays of selected potential lead molecules with commercially available panel of 26 kinases of same family. A distinctive kinase selectivity profile was observed for each compound. The selective compounds were identified with submicromolar cellular activity against MARK4. Furthermore, in vitro antitumor evaluation against cancerous cells (MCF-7 and HepG2) revealed that compounds 7b, 7d and 7f inhibit cell proliferation and predominantly induce apoptosis in MCF-7 cells, with IC(50) values of 5.2 ± 1.2 μM, 6.3 ± 1.2 μM, and 5.8 ± 1.4 μM respectively. In addition, these compounds significantly upsurge the oxidative stress in cancerous cells. Our observations support our approach for the synthesis of effective inhibitors against MARK4 that can be taken forward for the development of novel anticancer molecules targeting MARK4. Nature Publishing Group UK 2019-02-08 /pmc/articles/PMC6368574/ /pubmed/30737440 http://dx.doi.org/10.1038/s41598-018-38217-8 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Voura, Maria Khan, Parvez Thysiadis, Savvas Katsamakas, Sotiris Queen, Aarfa Hasan, Gulam Mustafa Ali, Sher Sarli, Vasiliki Hassan, Md. Imtaiyaz Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title | Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title_full | Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title_fullStr | Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title_full_unstemmed | Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title_short | Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones |
title_sort | probing the inhibition of microtubule affinity regulating kinase 4 by n-substituted acridones |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368574/ https://www.ncbi.nlm.nih.gov/pubmed/30737440 http://dx.doi.org/10.1038/s41598-018-38217-8 |
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