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6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury
Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Recep...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635128/ https://www.ncbi.nlm.nih.gov/pubmed/29018243 http://dx.doi.org/10.1038/s41598-017-12788-4 |
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author | Delehouzé, C. Leverrier-Penna, S. Le Cann, F. Comte, A. Jacquard-Fevai, M. Delalande, O. Desban, N. Baratte, B. Gallais, I. Faurez, F. Bonnet, M. C. Hauteville, M. Goekjian, P. G. Thuillier, R. Favreau, F. Vandenabeele, P. Hauet, T. Dimanche-Boitrel, M. T. Bach, S. |
author_facet | Delehouzé, C. Leverrier-Penna, S. Le Cann, F. Comte, A. Jacquard-Fevai, M. Delalande, O. Desban, N. Baratte, B. Gallais, I. Faurez, F. Bonnet, M. C. Hauteville, M. Goekjian, P. G. Thuillier, R. Favreau, F. Vandenabeele, P. Hauet, T. Dimanche-Boitrel, M. T. Bach, S. |
author_sort | Delehouzé, C. |
collection | PubMed |
description | Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis. |
format | Online Article Text |
id | pubmed-5635128 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56351282017-10-18 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury Delehouzé, C. Leverrier-Penna, S. Le Cann, F. Comte, A. Jacquard-Fevai, M. Delalande, O. Desban, N. Baratte, B. Gallais, I. Faurez, F. Bonnet, M. C. Hauteville, M. Goekjian, P. G. Thuillier, R. Favreau, F. Vandenabeele, P. Hauet, T. Dimanche-Boitrel, M. T. Bach, S. Sci Rep Article Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis. Nature Publishing Group UK 2017-10-10 /pmc/articles/PMC5635128/ /pubmed/29018243 http://dx.doi.org/10.1038/s41598-017-12788-4 Text en © The Author(s) 2017 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 Delehouzé, C. Leverrier-Penna, S. Le Cann, F. Comte, A. Jacquard-Fevai, M. Delalande, O. Desban, N. Baratte, B. Gallais, I. Faurez, F. Bonnet, M. C. Hauteville, M. Goekjian, P. G. Thuillier, R. Favreau, F. Vandenabeele, P. Hauet, T. Dimanche-Boitrel, M. T. Bach, S. 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title | 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title_full | 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title_fullStr | 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title_full_unstemmed | 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title_short | 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury |
title_sort | 6e11, a highly selective inhibitor of receptor-interacting protein kinase 1, protects cells against cold hypoxia-reoxygenation injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635128/ https://www.ncbi.nlm.nih.gov/pubmed/29018243 http://dx.doi.org/10.1038/s41598-017-12788-4 |
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