ArticleChemMedChem2022
The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors.
Article in ChemMedChem, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 26 citations in OpenAlex.
- MTHFD2: a promising metabolic checkpoint for diseases.Journal of translational medicine · 2026Review
- MTHFD1L is a novel prognostic marker and therapeutic target in cutaneous melanoma.Diagnostic pathology · 2025Article
- Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L.Scientific reports · 2024Article
- Cycling back to folate metabolism in cancer.Nature cancer · 2024Review
- Article
- Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.Nature metabolism · 2023Article
- Whether MTHFD2 plays a new role: from anticancer targets to anti-inflammatory disease.Frontiers in pharmacology · 2023Article
- Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma.Journal of translational medicine · 2022Article
- The First Structure of Human MTHFD2L and Its Implications for the Development of Isoform-Selective Inhibitors.ChemMedChem · 2022Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial 1-carbon metabolism enzyme, which is an attractive anticancer drug target as it is highly upregulated in cancer but is not expressed in healthy adult cells. Selective MTHFD2 inhibitors could therefore offer reduced side-effects during treatment, which are common with antifolate drugs that target other 1C-metabolism enzymes. This task is challenging however, as MTHFD2 shares high sequence identity with the constitutively expressed isozymes cytosolic MTHFD1 and mitochondrial MTHFD2L. In fact, one of the most potent MTHFD2 inhibitors reported to date, TH7299, is actually more active against MTHFD1 and MTHFD2L. While structures of MTHFD2 and MTHFD1 exist, no MTHFD2L structures are available. We determined the first structure of MTHFD2L and its complex with TH7299, which reveals the structural basis for its highly potent MTHFD2L inhibition. Detailed analysis of the MTHFD2L structure presented here clearly highlights the challenges associated with developing truly isoform-selective MTHFD2 inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.