A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
Open accessAbstract
Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Small-molecule inhibitors targeting PHGDH inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models.
“and small-molecule inhibitors targeting PHGDH have been shown to inhibit serine synthesis and tumor proliferation in vitro and in xenograft cancer models (Mullarky et al., 2016; Pacold et al., 2016; Wang et al., 2017).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Pacold et al., 2016
Many PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of PHGDH, but for some tumor models PHGDH expression is dispensable for growth.
“Similarly, many PHGDH-amplified tumors and cell lines are sensitive to genetic or pharmacological inhibition of the enzyme (Locasale et al., 2011; Mullarky et al., 2016; Pacold et al., 2016; Possemato et al., 2011; Wang et al., 2017; Zhang et al., 2017), but for some tumor models PHGDH expression can be dispensable for growth (Chen et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Pacold et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 35 · Cited by 553
Research works printed but not linked: 2
- [24]Di L Kerns EH Augustijns P Brewster ME Solvent Systems and their Selection in Pharmaceutics and Biopharmaceutics 2007 New York Springer
- [27]Walsh MJ ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model 2010 National Center for Biotechnology Information (US) 23905203
- Authors
- Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., Possemato, R., Chen, W. W., Sullivan, L. B., Fiske, B. P., Cho, S., Freinkman, E., Birsoy, K., Abu-Remaileh, M., Shaul, Y. D., Liu, C. M., Zhou, M., Koh, M. J., Chung, H., Davidson, S. M., Luengo, A., Wang, A. Q., Xu, X., Yasgar, A., Liu, L., Rai, G., Westover, K. D., Vander Heiden, M. G., Shen, M., Gray, N. S., Boxer, M. B., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- National Institutes of Health (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- NYU Langone Health (US)
- Whitehead Institute for Biomedical Research (US)
- Rockefeller University (US)
- Hebrew University of Jerusalem (IL)
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Sabatini, David M
- ORCID
- Pacold, Michael E
- Brimacombe, Kyle R
- Chan, Sze Ham
- Rohde, Jason M
- Lewis, Caroline A
- Swier, Lotteke J Y M
- Possemato, Richard
- Chen, Walter W
- Sullivan, Lucas B
- Fiske, Brian P
- Cho, Steve
- Birsoy, Kıvanç
- Abu-Remaileh, Monther
- Shaul, Yoav D
- Zhou, Minerva
- Koh, Min Jung
- Chung, Haeyoon
- Davidson, Shawn M
- Luengo, Alba
- Wang, Amy Q
- Xu, Xin
- Yasgar, Adam
- Rai, Ganesha
- Westover, Kenneth D
- Shen, Min
- Gray, Nathanael S
- Sabatini, David M
- Venue
- Nature Chemical Biology
- Published
- 2016-04-25
- Volume
- 12
- Issue
- 6
- Pages
- 452-458
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC4871733
- OpenAlex
- W2343452853
- Cited by
- 553
- References
- 35
- Citations by year
- 2026: 41 · 2025: 62 · 2024: 62 · 2023: 65 · 2022: 60 · 2021: 77 · 2020: 71 · 2019: 42 · 2018: 28 · 2017: 26 · 2016: 19
- FWCI
- 16.39
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-07-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (W81XWH)
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation (DRG-112-12)
- Alexander and Margaret Stewart Trust
- National Institutes of Health (W81XWH, CA129105, AI047389)
- National Institute on Drug Abuse (R03DA034602)
- National Cancer Institute (R21CA198028, R01CA103866, K22CA193660, R01CA168653, R01CA129105, P30CA014051)
- National Institute of General Medical Sciences (T32GM007753, T32GM007287)
- National Institute of Allergy and Infectious Diseases (R37AI047389)
- Lawrence Berkeley National Laboratory
- DOD Peer Reviewed Cancer Research Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- PHGDH, serine biosynthesis, one-carbon units, nucleotide synthesis, de novo purine synthesis, breast cancer, small molecule inhibitors, tumor xenografts
- MeSH terms
- Animals, Carbon, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Glycolysis, Humans, Mammary Neoplasms, Experimental, Purines, Serine, Structure-Activity Relationship, Thymidine, Tumor Cells, Cultured, Molecular Structure, Xenograft Model Antitumor Assays, Cell Proliferation, Phosphoglycerate Dehydrogenase, Mice, Small Molecule Libraries
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
