ArticleProceedings of the National Academy of Sciences of the United States of America2001
Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 28 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 138 citations in OpenAlex.
- Intra-cluster receptor density (IRD): A molecular switch for TNFR1 clusters' signaling.Science advances · 2026Article
- Discovery of Ligands for the TNFR1 Extracellular Domain Using Fragment-Based Drug Discovery.ChemMedChem · 2026Article
- Selective Inhibition of Tumor Necrosis Factor for Attenuating Alzheimer's Disease: Strategies Targeting Neuroinflammation.Inflammation · 2026Review
- Targeting the inter-monomeric space of TNFR1 pre-ligand dimers: A novel binding pocket for allosteric modulators.Computational and structural biotechnology journal · 2025Article
- New pyrazole-pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking,RSC medicinal chemistry · 2024Article
- Green design and synthesis of some novel thiazolidinone appended benzothiazole-triazole hybrids as antimicrobial agents.RSC advances · 2024Article
- A novel TNFRSF1A mutation associated with TNF-receptor-associated periodic syndrome and its metabolic signature.Rheumatology (Oxford, England) · 2023Article
- Zafirlukast Is a Promising Scaffold for Selectively Inhibiting TNFR1 Signaling.ACS bio & med chem Au · 2023Article
- Drug repurposing based on the similarity gene expression signatures to explore for potential indications of quercetin: a case study of multiple sclerosis.Frontiers in chemistry · 2023Article
- Potent Alkaline Phosphatase Inhibitors, Pyrazolo-Oxothiazolidines: Synthesis, Biological Evaluation, Molecular Docking, and Kinetic Studies.International journal of molecular sciences · 2022Article
- Glycine is a competitive antagonist of the TNF receptor mediating the expression of inflammatory cytokines in 3T3-L1 adipocytes.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2021Article
- Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future.Genes & diseases · 2021Review
- Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments.Journal of biosciences · 2019Article
- Noncompetitive inhibitors of TNFR1 probe conformational activation states.Science signaling · 2019Article
- Antioxidant and immunomodulatory activity induced by stevioside in liver damage: In vivo, in vitro and in silico assays.Life sciences · 2019Article
- Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids.European journal of medicinal chemistry · 2016Review
- Identification and characterization of novel inhibitors of Mammalian aspartyl aminopeptidase.Molecular pharmacology · 2014Article
- A novel small-molecule tumor necrosis factor α inhibitor attenuates inflammation in a hepatitis mouse model.The Journal of biological chemistry · 2014Article
- TWEAK/Fn14 Axis-Targeted Therapeutics: Moving Basic Science Discoveries to the Clinic.Frontiers in immunology · 2013Article
- Synthesis and biological activity evaluation of 5-pyrazoline substituted 4-thiazolidinones.European journal of medicinal chemistry · 2013Article
Corrections and comments
- Erratum issuedMuckelbauer JA [corrected to Muckelbauer JK]
Authors and funding
27 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.
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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.