{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Rana S"],"funding":["Intramural NIH HHS","NCATS NIH HHS","NCI NIH HHS"],"pagination":["221-233.e14"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922102"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["31(2)"],"pubmed_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. Importa"],"journal":["Cell chemical biology"],"pubmed_title":["Methotrexate-based PROTACs as DHFR-specific chemical probes."],"pmcid":["PMC10922102"],"funding_grant_id":["ZIA BC009287","U54 CA274329","Z01 BC009287","ZIA TR000053","R43 TR000471","R01 CA270234","R01 CA256911","R01 CA163649"],"pubmed_authors":["Wilson KM","Inglese J","Rana S","Singh PK","Rajacharya GH","Oliphant E","Dranchak P","Durum SK","Tao D","Holland DO","Li W","Rai G","Dahlin JL","Whitten AS","Lamy L","Tharakan R","Shrimp JH"],"additional_accession":[]},"is_claimable":false,"name":"Methotrexate-based PROTACs as DHFR-specific chemical probes.","description":"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. Importa","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2026-06-01T21:56:20.589Z","creation":"2025-04-04T02:54:32.015Z"},"accession":"S-EPMC10922102","cross_references":{"pubmed":["37875111"],"doi":["10.1016/j.chembiol.2023.09.014"]}}