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Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosp...

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Autores principales: Spillier, Quentin, Ravez, Séverine, Unterlass, Judith, Corbet, Cyril, Degavre, Charline, Feron, Olivier, Frédérick, Raphaël
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168936/
https://www.ncbi.nlm.nih.gov/pubmed/31979167
http://dx.doi.org/10.3390/ph13020020
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author Spillier, Quentin
Ravez, Séverine
Unterlass, Judith
Corbet, Cyril
Degavre, Charline
Feron, Olivier
Frédérick, Raphaël
author_facet Spillier, Quentin
Ravez, Séverine
Unterlass, Judith
Corbet, Cyril
Degavre, Charline
Feron, Olivier
Frédérick, Raphaël
author_sort Spillier, Quentin
collection PubMed
description For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.
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spelling pubmed-71689362020-04-20 Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH) Spillier, Quentin Ravez, Séverine Unterlass, Judith Corbet, Cyril Degavre, Charline Feron, Olivier Frédérick, Raphaël Pharmaceuticals (Basel) Article For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH. MDPI 2020-01-22 /pmc/articles/PMC7168936/ /pubmed/31979167 http://dx.doi.org/10.3390/ph13020020 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Spillier, Quentin
Ravez, Séverine
Unterlass, Judith
Corbet, Cyril
Degavre, Charline
Feron, Olivier
Frédérick, Raphaël
Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title_full Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title_fullStr Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title_full_unstemmed Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title_short Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)
title_sort structure–activity relationships (sars) of α-ketothioamides as inhibitors of phosphoglycerate dehydrogenase (phgdh)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168936/
https://www.ncbi.nlm.nih.gov/pubmed/31979167
http://dx.doi.org/10.3390/ph13020020
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