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

Scientific reports 2019 Mar 18

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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.

Citation

Quentin Spillier, Didier Vertommen, Séverine Ravez, Romain Marteau, Quentin Thémans, Cyril Corbet, Olivier Feron, Johan Wouters, Raphaël Frédérick. Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation. Scientific reports. 2019 Mar 18;9(1):4737