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Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma
Open accessAbstract
Significance Enzymes of the folate cycle are among the most consistently overexpressed proteins in cancer. Whereas multiple clinical agents inhibit thymidylate synthase, no current drugs target the incorporation of one-carbon into folates via serine hydroxymethyltransferase (SHMT). Using genetics, we show that cancer cells require SHMT to generate tumors. We then describe small-molecule SHMT inhibitors, and show that they block the growth of many human cancer cells, with B-cell lymphomas particularly sensitive to SHMT inhibition. We find that this sensitivity arises from the lymphomas’ inability to import the amino acid glycine, which is made as a byproduct of the SHMT reaction. Thus, B-cell lymphomas have an intrinsic defect in amino acid import, which causes a therapeutically targetable metabolic vulnerability.
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“Further optimization of this scaffold led to potent inhibitors of both SHMT1 and SHMT2.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [143]
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“Prior to Nonaka and co-worker’s study, generally, only marginal selectivity between the two SHMT isoforms has been achieved, with the inhibitors being selective for SHMT1 by 2- to 3-fold.”
From A review of small-molecule inhibitors of one-carbon enzymes: SHMT2 and MTHFD2 in the spotlight (2021) · cites this paper as [143]
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Metadata
- Authors
- Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Raze Therapeutics, Cambridge, MA 02139;
- Department of Molecular Biology, Princeton University, Princeton NJ 08544;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-10-09
- Volume
- 114
- Issue
- 43
- Pages
- 11404-11409
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5664509
- OpenAlex
- W2761750372
- Cited by
- 261
- References
- 35
- Citations by year
- 2026: 26 · 2025: 29 · 2024: 30 · 2023: 39 · 2022: 29 · 2021: 36 · 2020: 34 · 2019: 26 · 2018: 12
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (R01CA163591, K99CA215307)
- EIF | Stand Up To Cancer (SU2C) (SU2CAACR-DT-20-16)
- American Cancer Society (ACS) (PF-15-190-01-TBE)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- serine hydroxymethyltransferase, folate cycle, one-carbon metabolism, diffuse large B-cell lymphoma, metabolic vulnerability, small molecule inhibitors, cancer metabolism
- MeSH terms
- Animals, Binding Sites, Enzyme Inhibitors, Female, Glycine, Humans, Mice, Nude, Models, Molecular, Neoplasms, Experimental, Protein Conformation, Glycine Hydroxymethyltransferase, Molecular Structure, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, Gene Deletion, Cell Line, Tumor, Mice
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