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Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I

Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects...

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Autores principales: Stephenson, Zoe A, Harvey, Robert F, Pryde, Kenneth R, Mistry, Sarah, Hardy, Rachel E, Serreli, Riccardo, Chung, Injae, Allen, Timothy EH, Stoneley, Mark, MacFarlane, Marion, Fischer, Peter M, Hirst, Judy, Kellam, Barrie, Willis, Anne E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316505/
https://www.ncbi.nlm.nih.gov/pubmed/32432547
http://dx.doi.org/10.7554/eLife.55845
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author Stephenson, Zoe A
Harvey, Robert F
Pryde, Kenneth R
Mistry, Sarah
Hardy, Rachel E
Serreli, Riccardo
Chung, Injae
Allen, Timothy EH
Stoneley, Mark
MacFarlane, Marion
Fischer, Peter M
Hirst, Judy
Kellam, Barrie
Willis, Anne E
author_facet Stephenson, Zoe A
Harvey, Robert F
Pryde, Kenneth R
Mistry, Sarah
Hardy, Rachel E
Serreli, Riccardo
Chung, Injae
Allen, Timothy EH
Stoneley, Mark
MacFarlane, Marion
Fischer, Peter M
Hirst, Judy
Kellam, Barrie
Willis, Anne E
author_sort Stephenson, Zoe A
collection PubMed
description Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis.
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spelling pubmed-73165052020-06-29 Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I Stephenson, Zoe A Harvey, Robert F Pryde, Kenneth R Mistry, Sarah Hardy, Rachel E Serreli, Riccardo Chung, Injae Allen, Timothy EH Stoneley, Mark MacFarlane, Marion Fischer, Peter M Hirst, Judy Kellam, Barrie Willis, Anne E eLife Biochemistry and Chemical Biology Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a loss of cardiac function. An analysis of the effects of mubritinib on cardiac cells showed that this drug did not inhibit HER2 as reported, but directly inhibits mitochondrial respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure resulting in cell death. We used a library of chemical variants of mubritinib and showed that modifying the 1H-1,2,3-triazole altered complex I inhibition, identifying the heterocyclic 1,3-nitrogen motif as the toxicophore. The same toxicophore is present in a second anti-cancer therapeutic carboxyamidotriazole (CAI) and we demonstrate that CAI also functions through complex I inhibition, mediated by the toxicophore. Complex I inhibition is directly linked to anti-cancer cell activity, with toxicophore modification ablating the desired effects of these compounds on cancer cell proliferation and apoptosis. eLife Sciences Publications, Ltd 2020-05-20 /pmc/articles/PMC7316505/ /pubmed/32432547 http://dx.doi.org/10.7554/eLife.55845 Text en © 2020, Stephenson et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Stephenson, Zoe A
Harvey, Robert F
Pryde, Kenneth R
Mistry, Sarah
Hardy, Rachel E
Serreli, Riccardo
Chung, Injae
Allen, Timothy EH
Stoneley, Mark
MacFarlane, Marion
Fischer, Peter M
Hirst, Judy
Kellam, Barrie
Willis, Anne E
Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title_full Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title_fullStr Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title_full_unstemmed Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title_short Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I
title_sort identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex i
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316505/
https://www.ncbi.nlm.nih.gov/pubmed/32432547
http://dx.doi.org/10.7554/eLife.55845
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