Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation

Quentin Spillier, Didier Vertommen, Séverine Ravez, Romain Marteau, Quentin Thémans, Cyril Corbet, Olivier Feron, Johan Wouters, Raphaël Frédérick

Research output: Contribution to journalArticle

Abstract

Due to rising costs and the difficulty to identify new targets, drug repurposing appears as a viable strategy for the development of new anti-cancer treatments. Although the interest of disulfiram (DSF), an anti-alcohol drug, to treat cancer was reported for many years, it is only very recently that one anticancer mechanism-of-action was highlighted. This would involve the inhibition of the p97 segregase adaptor NPL4, which is essential for the turnover of proteins involved in multiple regulatory and stress-response intracellular pathways. However, recently DSF was also reported as one of the first phosphoglycerate dehydrogenase (PHGDH) inhibitors, a tetrameric enzyme catalyzing the initial step of the serine synthetic pathway that is highly expressed in numerous cancer types. Here, we investigated the structure-activity relationships (SAR) of PHGDH inhibition by disulfiram analogues as well as the mechanism of action of DSF on PHGDH via enzymatic and cell-based evaluation, mass spectrometric and mutagenesis experiments.

Original languageEnglish
Article number4737
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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Phosphoglycerate Dehydrogenase
Disulfiram
Alcoholism
Cysteine
Pharmaceutical Preparations
Drug Repositioning
Neoplasms
Structure-Activity Relationship
Mutagenesis
Serine
Alcohols
Costs and Cost Analysis
Enzymes
Proteins

Cite this

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title = "Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation",
abstract = "Due to rising costs and the difficulty to identify new targets, drug repurposing appears as a viable strategy for the development of new anti-cancer treatments. Although the interest of disulfiram (DSF), an anti-alcohol drug, to treat cancer was reported for many years, it is only very recently that one anticancer mechanism-of-action was highlighted. This would involve the inhibition of the p97 segregase adaptor NPL4, which is essential for the turnover of proteins involved in multiple regulatory and stress-response intracellular pathways. However, recently DSF was also reported as one of the first phosphoglycerate dehydrogenase (PHGDH) inhibitors, a tetrameric enzyme catalyzing the initial step of the serine synthetic pathway that is highly expressed in numerous cancer types. Here, we investigated the structure-activity relationships (SAR) of PHGDH inhibition by disulfiram analogues as well as the mechanism of action of DSF on PHGDH via enzymatic and cell-based evaluation, mass spectrometric and mutagenesis experiments.",
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Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation. / Spillier, Quentin; Vertommen, Didier; Ravez, Séverine; Marteau, Romain; Thémans, Quentin; Corbet, Cyril; Feron, Olivier; Wouters, Johan; Frédérick, Raphaël.

In: Scientific Reports, Vol. 9, No. 1, 4737, 01.12.2019.

Research output: Contribution to journalArticle

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AU - Spillier, Quentin

AU - Vertommen, Didier

AU - Ravez, Séverine

AU - Marteau, Romain

AU - Thémans, Quentin

AU - Corbet, Cyril

AU - Feron, Olivier

AU - Wouters, Johan

AU - Frédérick, Raphaël

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