ArticleNature cancer2022
Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.
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Article in Nature cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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59 citing papers in PubMed, 101 citations in OpenAlex.
- The mitochondrial chaperone HSPD1 folds MTHFD2 independently of its co-chaperone HSPE1.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Article
- Ribonucleotides Amplify Mitochondrial DNA-Driven cGAS-STING Activation via FdUMP-ribonucleotide Hybrid Particles to Potentiate Chemoimmunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- A five-gene TAM and MYCN signature predicts prognosis and identifies MTHFD2 as a therapeutic target in neuroblastoma.Discover oncology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Targeting the cancer metabolism-immunity interface: update and perspectives.Experimental hematology & oncology · 2026Review
- Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis.Signal transduction and targeted therapy · 2026Article
- Hierarchies of resistance to DNA damage response inhibitors: from pathway restoration to replication stress tolerance.Experimental hematology & oncology · 2026Review
- Uridine cytidine kinases govern molnupiravir bioactivation and anti-SARS-CoV-2 activity.PLoS pathogens · 2026Article
- MTHFD2: a promising metabolic checkpoint for diseases.Journal of translational medicine · 2026Review
- The oncogenic control of nucleotide synthesis.Oncogenesis · 2026Review
- Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.npj metabolic health and disease · 2026Review
- SOX4-STAT6-MTHFD2 axis drives hepatocellular carcinoma progression and treatment resistance.Cell death & disease · 2026Article
- The tumor microenvironment of medulloblastoma: from emerging biological insights to novel therapeutic targeting.Frontiers in oncology · 2026Review
- Metabolic adaptations in cancer progression.Physiological reviews · 2026Review
- One size does not fit all: A comparative framework for optimizing ribonucleic acid transfection across acute myeloid leukemia cell lines.Biology methods & protocols · 2026Article
- Dissecting the Dual Drug Candidates Against Glioblastoma and Oligodendroglioma Through Integrated Transcriptome Analysis and Virtual Screening.Cell biochemistry and biophysics · 2025Article
- WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response.Nature communications · 2025Article
- MTHFD2: A Retrospective and a Glance into the Future.International journal of molecular sciences · 2025Review
- Causal Effects of Plasma Metabolites on Leukemia: A Mendelian Randomization Study.Metabolites · 2025Article
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Authors and funding
68 authors at 8 institutions in 5 countries.
Nadilly Bonagas *Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.ORCID http://orcid.org/0000-0001-7336-4065
Nina M S Gustafsson *Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Martin Henriksson *Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Petra Marttila *Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.ORCID http://orcid.org/0000-0002-0115-8067
Robert GustafssonDepartment of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-4854-5531
Elisée WiitaScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Sanjay BorhadeScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Alanna C GreenWeston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.
Karl S A VallinScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Antonio SarnoDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Richard SvenssonUppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Camilla GöktürkScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Therese PhamScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Ann-Sofie JemthScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.ORCID http://orcid.org/0000-0002-7550-1833
Olga LosevaScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Victoria CooksonWeston Park Cancer Centre, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0003-3089-4837
Nicole KiwelerCancer Metabolism Group, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.ORCID http://orcid.org/0000-0001-7493-703X
Lars SandbergDrug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
Azita RastiScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Judith E UnterlassScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Martin HaraldssonDrug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
Yasmin AnderssonDrug Discovery and Development Platform, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology, Solna, Sweden.
Emma R ScalettiDepartment of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.
Christoffer BengtssonDrug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
Cynthia B J PaulinScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Kumar SanjivScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Eldar AbdurakhmanovDrug Discovery and Development Platform, Science for Life Laboratory, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
Linda PudelkoScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Ben KunzScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Matthieu DesrosesScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Petar IlievScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Katarina FärnegårdhDrug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
Andreas KrämerInstitute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.ORCID http://orcid.org/0000-0003-3294-2660
Neeraj GargDepartment of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Maurice MichelScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Sara HäggbladBiochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Malin JarviusDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
Christina KalderénScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Amanda Bögedahl JensenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Ingrid AlmlöfScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Stella KarstenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.ORCID http://orcid.org/0000-0001-6191-4314
Si Min ZhangScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Maria HäggbladBiochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Anders ErikssonKarolinska High Throughput Centre, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Jianping LiuKarolinska High Throughput Centre, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.ORCID http://orcid.org/0000-0002-7336-3895
Björn GlinghammarDrug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
Natalia NekhotiaevaKarolinska High Throughput Centre, Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Fredrik KlingegårdDrug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
Tobias KoolmeisterScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Ulf MartensBiochemical and Cellular Screening Facility, Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden.
Sabin Llona-MinguezScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Ruth MoulsonScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Helena NordströmDrug Discovery and Development Platform, Science for Life Laboratory, Department of Chemistry-BMC, Uppsala University, Uppsala, Sweden.
Vendela ParrowDepartment of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden.
Leif DahllundDrug Discovery and Development Platform, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Royal Institute of Technology, Solna, Sweden.
Birger SjöbergDrug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
Irene L VargasScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Duy Duc VoDepartment of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Johan WannbergDepartment of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.ORCID http://orcid.org/0000-0001-5494-0848
Stefan KnappInstitute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.ORCID http://orcid.org/0000-0001-5995-6494
Hans E KrokanDepartment of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
Per I ArvidssonDrug Discovery and Development Platform, Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.ORCID http://orcid.org/0000-0002-9453-6812
Martin ScobieScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Johannes MeiserCancer Metabolism Group, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Pål StenmarkDepartment of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-4777-3417
Ulrika Warpman BerglundScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Evert J HomanScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
Thomas HelledayScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. thomas.helleday@scilifelab.se.ORCID http://orcid.org/0000-0002-7384-092X
Science for Life Laboratory · SEStockholm University · SEUppsala University · SEKarolinska Institutet · SEGoethe University Frankfurt · DELuxembourg Institute of Health · LUNorwegian University of Science and Technology · NOWeston Park Cancer Centre · GB
Funding
No grant is acknowledged in the PubMed record.
Abstract
The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.
Indexed as
AminohydrolasesLeukemia, Myeloid, AcuteHumansHydrolasesMethylenetetrahydrofolate Dehydrogenase (NADP)Multifunctional EnzymesThymidineAminohydrolasesHydrolasesMethylenetetrahydrofolate Dehydrogenase (NADP)MTHFD2 protein, humanMultifunctional EnzymesThymidine
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