Anti-alcohol abuse drug disulfiram inhibits human PHGDH via disruption of its active tetrameric form through a specific cysteine oxidation
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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.
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Non-metabolized circulating DIS could also provide anticancer activity through PHGDH inhibition.
“Thus, the non-metabolized circulating DIS could also provide anticancer activity, but through a completely different mechanism of action involving PHGDH inhibition.85”
From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [85]
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- Authors
- Spillier, Q., Vertommen, D., Ravez, S., Marteau, R., Thémans, Q., Corbet, C., Feron, O., Wouters, J., & Frédérick, R.
- Affiliations
- UCLouvain (BE)
- de Duve Institute (BE)
- Inserm (FR)
- University of Namur (BE)
- Corresponding author
- Frédérick, Raphaël
- ORCID
- Venue
- Scientific Reports
- Published
- 2019-03-18
- Volume
- 9
- Issue
- 1
- Pages
- 4737-4737
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC6426982
- OpenAlex
- W2924545713
- Cited by
- 62
- References
- 23
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 10 · 2021: 11 · 2020: 10 · 2019: 5
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Repository of the University of Namur (submittedVersion, cc-by)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- disulfiram, PHGDH, cysteine oxidation, tetrameric enzyme structure, serine biosynthesis, drug repurposing, anticancer drug targets, structure-activity relationship, mechanism of action
- MeSH terms
- Alcohol Deterrents, Antineoplastic Agents, Cysteine, Disulfiram, Humans, Oxidation-Reduction, Structure-Activity Relationship, Phosphoglycerate Dehydrogenase, Protein Multimerization, Drug Repositioning
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