Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation.
Sci Rep
; 9(1): 4737, 2019 03 18.
Article
em En
| MEDLINE
| ID: mdl-30894617
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Cisteína
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Dissulfiram
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Fosfoglicerato Desidrogenase
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Multimerização Proteica
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Antineoplásicos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article