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Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors
The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cel...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594721/ https://www.ncbi.nlm.nih.gov/pubmed/33086897 http://dx.doi.org/10.1080/14756366.2020.1833876 |
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author | Kang, Seok Jong Lee, Jung Wuk Song, Jiho Park, Jiwon Choi, Jaeyul Suh, Kwee Hyun Min, Kyung Hoon |
author_facet | Kang, Seok Jong Lee, Jung Wuk Song, Jiho Park, Jiwon Choi, Jaeyul Suh, Kwee Hyun Min, Kyung Hoon |
author_sort | Kang, Seok Jong |
collection | PubMed |
description | The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC(50) of 27 nM. It showed a reversible reaction with β-mercaptoethanol, which supports its potential as a reversible covalent inhibitor. |
format | Online Article Text |
id | pubmed-7594721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-75947212020-11-10 Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors Kang, Seok Jong Lee, Jung Wuk Song, Jiho Park, Jiwon Choi, Jaeyul Suh, Kwee Hyun Min, Kyung Hoon J Enzyme Inhib Med Chem Brief Report The importance of transforming growth factor beta-activated kinase 1 (TAK1) to cell survival has been demonstrated in many studies. TAK1 regulates signalling cascades, the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway. TAK1 inhibitors can induce the apoptosis of cancerous cells, and irreversible inhibitors such as (5Z)-7-oxozeaenol are highly potent. However, they can react non-specifically with cysteine residues in proteins, which may have serious adverse effects. Reversible covalent inhibitors have been suggested as alternatives. We synthesised imidazopyridine derivatives as novel TAK1 inhibitors, which have 2-cyanoacrylamide moiety that can form reversible covalent bonding. A derivative with 2-cyano-3-(6-methylpyridin-2-yl)acrylamide (13h) exhibited potent TAK1 inhibitory activity with an IC(50) of 27 nM. It showed a reversible reaction with β-mercaptoethanol, which supports its potential as a reversible covalent inhibitor. Taylor & Francis 2020-10-22 /pmc/articles/PMC7594721/ /pubmed/33086897 http://dx.doi.org/10.1080/14756366.2020.1833876 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://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/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Brief Report Kang, Seok Jong Lee, Jung Wuk Song, Jiho Park, Jiwon Choi, Jaeyul Suh, Kwee Hyun Min, Kyung Hoon Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title | Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title_full | Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title_fullStr | Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title_full_unstemmed | Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title_short | Synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as TAK1 inhibitors |
title_sort | synthesis and biological activity of 2-cyanoacrylamide derivatives tethered to imidazopyridine as tak1 inhibitors |
topic | Brief Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594721/ https://www.ncbi.nlm.nih.gov/pubmed/33086897 http://dx.doi.org/10.1080/14756366.2020.1833876 |
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