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Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1
INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affin...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688747/ https://www.ncbi.nlm.nih.gov/pubmed/34949914 http://dx.doi.org/10.2147/DDDT.S323077 |
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author | Bourafai-Aziez, Asma Benabderrahmane, Mohammed Paysant, Hippolyte Weiswald, Louis-Bastien Poulain, Laurent Carlier, Ludovic Ravault, Delphine Jouanne, Marie Coadou, Gaël Oulyadi, Hassan Voisin-Chiret, Anne-Sophie Sopková-de Oliveira Santos, Jana Sebban, Muriel |
author_facet | Bourafai-Aziez, Asma Benabderrahmane, Mohammed Paysant, Hippolyte Weiswald, Louis-Bastien Poulain, Laurent Carlier, Ludovic Ravault, Delphine Jouanne, Marie Coadou, Gaël Oulyadi, Hassan Voisin-Chiret, Anne-Sophie Sopková-de Oliveira Santos, Jana Sebban, Muriel |
author_sort | Bourafai-Aziez, Asma |
collection | PubMed |
description | INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. RESULTS: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. CONCLUSION: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor. |
format | Online Article Text |
id | pubmed-8688747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-86887472021-12-22 Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 Bourafai-Aziez, Asma Benabderrahmane, Mohammed Paysant, Hippolyte Weiswald, Louis-Bastien Poulain, Laurent Carlier, Ludovic Ravault, Delphine Jouanne, Marie Coadou, Gaël Oulyadi, Hassan Voisin-Chiret, Anne-Sophie Sopková-de Oliveira Santos, Jana Sebban, Muriel Drug Des Devel Ther Original Research INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. RESULTS: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. CONCLUSION: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor. Dove 2021-12-15 /pmc/articles/PMC8688747/ /pubmed/34949914 http://dx.doi.org/10.2147/DDDT.S323077 Text en © 2021 Bourafai-Aziez et al. https://creativecommons.org/licenses/by-nc/3.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/ (https://creativecommons.org/licenses/by-nc/3.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Bourafai-Aziez, Asma Benabderrahmane, Mohammed Paysant, Hippolyte Weiswald, Louis-Bastien Poulain, Laurent Carlier, Ludovic Ravault, Delphine Jouanne, Marie Coadou, Gaël Oulyadi, Hassan Voisin-Chiret, Anne-Sophie Sopková-de Oliveira Santos, Jana Sebban, Muriel Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title_full | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title_fullStr | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title_full_unstemmed | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title_short | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
title_sort | drug repurposing: deferasirox inhibits the anti-apoptotic activity of mcl-1 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688747/ https://www.ncbi.nlm.nih.gov/pubmed/34949914 http://dx.doi.org/10.2147/DDDT.S323077 |
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