ArticleChemMedChem2018
Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma.
Article in ChemMedChem, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 73 citations in OpenAlex.
- Ferroptosis in skeletal muscle: from molecular mechanisms to therapeutic interventions.Journal of orthopaedic translation · 2026Review
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- CircHIPK2 recruits SRSF1 to increase TXNIP mRNA stability and promotes autophagy-dependent ferroptosis and apoptosis in myocardial ischemia-reperfusion injury.Journal of cardiothoracic surgery · 2025Article
- Nrf2/Keap1/ARE regulation by plant secondary metabolites: a new horizon in brain tumor management.Cell communication and signaling : CCS · 2024Review
- The unfolded protein response machinery in glioblastoma genesis, chemoresistance and as a druggable target.CNS neuroscience & therapeutics · 2024Review
- The tumour microenvironment, treatment resistance and recurrence in glioblastoma.Journal of translational medicine · 2024Review
- Inhibition of Protein Disulfide Isomerase Attenuates Osteoclast Differentiation and Function via the Readjustment of Cellular Redox State in Postmenopausal Osteoporosis.Inflammation · 2024Article
- Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival.International journal of molecular sciences · 2024Article
- Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.Scientific reports · 2024Article
- Early growth response 1 transcription factor and its context-dependent functions in glioblastoma.Contemporary oncology (Poznan, Poland) · 2024Review
- Pan-Inhibition of Protein Disulfide Isomerase Caused Cell Death through Disrupting Cellular Proteostasis in Pancreatic Ductal Adenocarcinoma Cells.International journal of molecular sciences · 2023Article
- Protein Disulfide Isomerase A3 (PDIA3): A Pharmacological Target in Glioblastoma?International journal of molecular sciences · 2023Article
- The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.Bioorganic & medicinal chemistry · 2023Article
- MicroRNA miR-378-3p is a novel regulator of endothelial autophagy and function.Journal of molecular and cellular cardiology plus · 2023Article
- Inhibition of Protein Disulfide Isomerase (PDIA1) Leads to Proteasome-Mediated Degradation of Ubiquitin-like PHD and RING Finger Domain-Containing Protein 1 (UHRF1) and Increased Sensitivity of Glioblastoma Cells to Topoisomerase II Inhibitors.ACS pharmacology & translational science · 2023Article
- Protein disulfide isomerase family mediated redox regulation in cancer.Advances in cancer research · 2023Review
- Ferroptosis-based drug delivery system as a new therapeutic opportunity for brain tumors.Frontiers in oncology · 2023Review
- Protein disulfide isomerase blocks the interaction of LC3II-PHB2 and promotes mTOR signaling to regulate autophagy and radio/chemo-sensitivity.Cell death & disease · 2022Article
- Emerging roles of cystathionine β-synthase in various forms of cancer.Redox biology · 2022Review
- Identification and validation of a ferroptosis-related prognostic risk-scoring model and key genes in small cell lung cancer.Translational lung cancer research · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.
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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.