Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers
Open accessAbstract
Significance: Serine supports a number of anabolic processes, including protein, lipid, and nucleic acid synthesis. Cells can either import serine or synthesize it de novo. Recently, overexpression of 3-phosphoglycerate dehydrogenase ( PHGDH ), the gene encoding the first committed step of serine synthesis, via focal amplification and other mechanisms, has been identified in human cancers. Cancer cell lines that overexpress PHGDH are uniquely sensitive to PHGDH knockdown whereas lines that express little PHGDH are insensitive, suggesting that PHGDH may be a clinically interesting target. Here, we report the discovery of a specific small molecule inhibitor of PHGDH, which enables preclinical evaluation of PHGDH as a target in cancer and provides a tool to study the biology of de novo serine synthesis.
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Serine-dependent redox homeostasis regulates glioblastoma cell survival
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High Expression of PHGDH Predicts Poor Prognosis in Non–Small Cell Lung Cancer
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A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight
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Phosphoserine Phosphatase Is a Novel Prognostic Biomarker on Chromosome 7 in Colorectal Cancer
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Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1
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- Authors
- Mullarky, E., Lucki, N. C., Beheshti Zavareh, R., Anglin, J. L., Gomes, A. P., Nicolay, B. N., Wong, J. C. Y., Christen, S., Takahashi, H., Singh, P. K., Blenis, J., Warren, J. D., Fendt, S.-M., Asara, J. M., DeNicola, G. M., Lyssiotis, C. A., Lairson, L. L., & Cantley, L. C.
- Affiliations
- Harvard University (US)
- California Institute for Biomedical Research (US)
- The California Institute for Biomedical Research, La Jolla, CA 92037;
- Weill Cornell Medicine (US)
- Vlaams Instituut voor Biotechnologie (BE)
- Beth Israel Deaconess Medical Center (US)
- University of Michigan (US)
- Scripps Research Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-02
- Volume
- 113
- Issue
- 7
- Pages
- 1778-1783
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4763784
- OpenAlex
- W2266570683
- Cited by
- 333
- References
- 38
- Citations by year
- 2026: 21 · 2025: 32 · 2024: 28 · 2023: 37 · 2022: 36 · 2021: 47 · 2020: 43 · 2019: 30 · 2018: 23 · 2017: 19 · 2016: 17
- FWCI
- 12.77
- Type
- journal article
- Language
- en
- Update notices
- correction (2016-03-07)
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Division of Cancer Prevention, National Cancer Institute (P01CA117969, P01CA120964)
- American Association for Cancer Research (13-70-25-LYSS, 14-70-25-DENI)
- 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
- 3-phosphoglycerate dehydrogenase, PHGDH, serine biosynthesis, small molecule inhibitors, cancer metabolism, tumor metabolic reprogramming, non-competitive inhibition, enzyme oligomerization, Nrf2, drug screening, anticancer drug discovery
- MeSH terms
- Humans, Neoplasms, Serine, Cell Line, Tumor, Cell Proliferation, Phosphoglycerate Dehydrogenase
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