ArticlePloS one2017
Pharmacological inhibition of RORγt suppresses the Th17 pathway and alleviates arthritis in vivo.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
- Selective disruption of RORγt-CBFβ interaction by IMU-935 prevents RORγt-dependent Th17 autoimmunity but not thymocyte development.The Journal of clinical investigation · 2026Article
- Fatty acid-related immune network in psoriasis: metabolic regulation of innate and adaptive immunity.Frontiers in pharmacology · 2026Review
- RORγt inverse agonists demonstrating a margin between inhibition of IL-17A and thymocyte apoptosis.PloS one · 2025Article
- The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis.International journal of molecular sciences · 2024Review
- Article
- The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.Cellular and molecular life sciences : CMLS · 2024Article
- JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis and Their Clinical Significance.Current rheumatology reports · 2024Review
- Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.Journal of medicinal chemistry · 2023Article
- Small molecule inhibitors of RORγt for Th17 regulation in inflammatory and autoimmune diseases.Journal of pharmaceutical analysis · 2023Review
- The Interleukine-17 Cytokine Family: Role in Development and Progression of Spondyloarthritis, Current and Potential Therapeutic Inhibitors.Biomedicines · 2023Review
- The role of retinoic acid receptor-related orphan receptors in skeletal diseases.Frontiers in endocrinology · 2023Review
- Identification of the Natural Steroid Sapogenin Diosgenin as a Direct Dual-Specific RORα/γ Inverse Agonist.Biomedicines · 2022Article
- Obesity and Fatty Acids Promote Mitochondrial Translocation of STAT3 Through ROS-Dependent Mechanisms.Frontiers in aging · 2022Article
- Joint together: The etiology and pathogenesis of ankylosing spondylitis.Frontiers in immunology · 2022Review
- Interference with the expression of S1PR1 or STAT3 attenuates valvular damage due to rheumatic heart disease.International journal of molecular medicine · 2021Article
- Lung eosinophils elicited during allergic and acute aspergillosis express RORγt and IL-23R but do not require IL-23 for IL-17 production.PLoS pathogens · 2021Article
- The heterogeneous human memory CCR6+ T helper-17 populations differ in T-bet and cytokine expression but all activate synovial fibroblasts in an IFNγ-independent manner.Arthritis research & therapy · 2021Article
- Discovery of a Series of Pyrazinone RORγ Antagonists and Identification of the Clinical Candidate BI 730357.ACS medicinal chemistry letters · 2021Article
- Interleukin-17 induced by cumulative mild stress promoted depression-like behaviors in young adult mice.Molecular brain · 2021Article
- Transcriptomic effects of rs4845604, an IBD and allergy-associated RORC variant, in stimulated ex vivo CD4+ T cells.PloS one · 2021Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Retinoic acid receptor-related-orphan-receptor-C (RORγt) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORγt in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim of inhibiting the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in vitro and in vivo pharmacology of a potent and selective small-molecular-weight RORγt inverse agonist. The compound binds to the ligand binding domain (LBD) of RORγt leading to displacement of a co-activator peptide. We show for the first time that a RORγt inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORγt-dependent genes. Consistent with this, the compound effectively reduced IL-17A production by polarized human T-cells and γδT-cells and attenuated transcription of RORγt target genes. The inhibitor showed good in vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex vivo recall assays. In summary, we demonstrate that inhibiting RORγt by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.
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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.