ArticleThe Journal of biological chemistry2022
The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 48 citations in OpenAlex.
- DORSSAA: Drug-Target interactOmics Resource Based on Stability/Solubility Alteration Assay.Molecular & cellular proteomics : MCP · 2026Article
- Beyond malaria prevention: sulfadoxine-pyrimethamine treatment in pregnancy selectively remodels the maternal gut microbiome to increase gestational weight gain and improve birthweight.medRxiv : the preprint server for health sciences · 2026Article
- Pyrimethamine Restores KEAP1-Mediated Degradation of Select NRF2 Mutants in Esophageal Squamous Cell Carcinoma.Cancers · 2026Article
- Salts of Antifolate Pyrimethamine with Isomeric Aminobenzoic Acids: Exploring Packing Interactions and Pre-Crystallization Aggregation.International journal of molecular sciences · 2025Article
- An mTOR-Stat3-Stathmin pathway controls centrosome and microtubule dynamics for oocyte polarization.Current biology : CB · 2025Article
- Combinatorial QM and MD in silico design of natural product-based DHFR inhibitors.Scientific reports · 2025Article
- The Road to Precision Nanomedicine: An Insight on Drug Repurposing and Advances in Nanoformulations for Treatment of Cancer.AAPS PharmSciTech · 2025Review
- Pyrimethamine Triggers the Apoptotic Pathway in Mucoepidermoid Carcinoma in Cell-Based Models.Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology · 2025Article
- Drug Repurposing for Kala-Azar.Pharmaceutics · 2025Article
- Anti-Toxoplasma gondii efficacy of beta, beta-dimethylacrylshikonin and isobutyrylshikonin in vitro and in vivo.Parasites & vectors · 2025Article
- BONCAT-iTRAQ Labelling Reveals Molecular Markers of Adaptive Responses inPathogens (Basel, Switzerland) · 2024Article
- Merging multi-omics with proteome integral solubility alteration unveils antibiotic mode of action.eLife · 2024Article
- Stability-based approaches in chemoproteomics.Expert reviews in molecular medicine · 2024Review
- Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells.Journal for immunotherapy of cancer · 2024Article
- Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.Cancers · 2024Review
- Computational workflow for discovering small molecular binders for shallow binding sites by integrating molecular dynamics simulation, pharmacophore modeling, and machine learning: STAT3 as case study.Journal of computer-aided molecular design · 2023Article
- Recent Advances in Transcription Factors Biomarkers and Targeted Therapies Focusing on Epithelial-Mesenchymal Transition.Cancers · 2023Review
- The Knowns and Unknowns in Protein-Metabolite Interactions.International journal of molecular sciences · 2023Review
- Discovery of new STAT3 inhibitors as anticancer agents using ligand-receptor contact fingerprints and docking-augmented machine learning.RSC advances · 2023Article
- Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity.Metabolites · 2023Article
Corrections and comments
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Authors and funding
16 authors at 9 institutions in 4 countries.
Funding
Abstract
Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers.
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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.