ArticleCell chemical biology2024
Methotrexate-based PROTACs as DHFR-specific chemical probes.
Article in Cell chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 15 citations in OpenAlex.
- Engineering Protein Stability with Small Molecules: A Review of the ecDHFR Destabilizing Domain System.ACS chemical biology · 2026Review
- Article
- Polyploid cancer cells surviving cisplatin reallocate central carbon sources to fuel antioxidant metabolism for survival.Molecular metabolism · 2026Article
- Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease.Pharmacological reviews · 2026Review
- Label-Free Target Discovery Strategy for Natural Active Products.Biomolecules · 2026Review
- Drug-tolerant persister cells reallocate carbon sources to fuel antioxidant metabolism for survival.bioRxiv : the preprint server for biology · 2026Article
- Innovative Therapies for Oncogenic KRAS Mutations: Precision Strategies with PROTACs in Cancer Treatment.Anti-cancer agents in medicinal chemistry · 2026Review
- One-carbon metabolism in cancer: moonlighting functions of metabolic enzymes and anti-tumor therapy.Cancer metastasis reviews · 2025Review
- New Insights into Pathogenesis and Management of Keratoacanthoma: A Narrative Review.International journal of molecular sciences · 2025Review
- A general assay platform to study protein pharmacology using ligand-dependent structural dynamics.Nature communications · 2025Article
- An anti-CD19-exosome delivery system navigates the blood-brain barrier for targeting of central nervous system lymphoma.Journal of nanobiotechnology · 2025Article
- ELK4 Promotes Vasculogenic Mimicry in Oral Squamous Cell Carcinoma via DrivingOncology research · 2025Article
- Combating Methotrexate Resistance in Cancer Treatment: A Review on Navigating Pathways and Enhancing Its Efficacy With Fat-Soluble Vitamins.Scientifica · 2025Review
- Utilizing small molecules to probe and harness the proteome by pooled protein tagging with ligandable domains.Frontiers in pharmacology · 2025Review
- Exploration of the link between COVID-19 and gastric cancer from the perspective of bioinformatics and systems biology.Frontiers in medicine · 2024Article
Corrections and comments
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Authors and funding
17 authors at 3 institutions in 1 country.
Funding
Abstract
Methotrexate (MTX) is a tight-binding dihydrofolate reductase (DHFR) inhibitor, used as both an antineoplastic and immunosuppressant therapeutic. MTX, like folate undergoes folylpolyglutamate synthetase-mediated γ-glutamylation, which affects cellular retention and target specificity. Mechanisms of MTX resistance in cancers include a decrease in MTX poly-γ-glutamylation and an upregulation of DHFR. Here, we report a series of potent MTX-based proteolysis targeting chimeras (PROTACs) to investigate DHFR degradation pharmacology and one-carbon biochemistry. These on-target, cell-active PROTACs show proteasome- and E3 ligase-dependent activity, and selective degradation of DHFR in multiple cancer cell lines. By comparison, treatment with MTX increases cellular DHFR protein expression. Importantly, these PROTACs produced distinct, less-lethal phenotypes compared to MTX. The chemical probe set described here should complement conventional DHFR inhibitors and serve as useful tools for studying one-carbon biochemistry and dissecting complex polypharmacology of MTX and related drugs. Such compounds may also serve as leads for potential autoimmune and antineoplastic therapeutics.
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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 Socratic graph.