Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma
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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 the pyrazolopyran scaffold led to potent inhibitors of both SHMT1 and SHMT2.
“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]
Prior to Nonaka and co-worker's study, only marginal selectivity between the two SHMT isoforms had been achieved, with inhibitors being selective for SHMT1 by 2- to 3-fold.
“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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- 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 › Medicine › Rheumatology › 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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