ArticleScientific reports2021
Discovery of a novel RORγ antagonist with skin-restricted exposure for topical treatment of mild to moderate psoriasis.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Psoriasis: A Multidimensional Review of Onset, Progression, Treatment, and the Evolution of Disease Models.Molecular diagnosis & therapy · 2025Review
- A High-Quality Photoswitchable Probe that Selectively and Potently Regulates the Transcription Factor RORγ.Angewandte Chemie (International ed. in English) · 2024Article
- The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis.International journal of molecular sciences · 2024Review
- Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis.Biomolecules · 2024Review
- Article
- Bibliometric analysis and description of research trends on T cells in psoriasis over the past two decades (2003-2022).Heliyon · 2024Article
- The IL-17 family in diseases: from bench to bedside.Signal transduction and targeted therapy · 2023Review
- 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
- An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.Scientific reports · 2022Article
- Adipose Tissue Immunomodulation and Treg/Th17 Imbalance in the Impaired Glucose Metabolism of Children with Obesity.Children (Basel, Switzerland) · 2021Review
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clinical success of IL-17/IL-23 pathway biologics for the treatment of moderate to severe psoriasis suggests that targeting RORγt, a master regulator for the proliferation and function of Th17 cells, could be an effective alternative. However, oral RORγ antagonists (VTP43742, TAK828) with high systemic exposure showed toxicity in phase I/II clinical trials and terminated development. To alleviate the potential safety concerns, identifying compounds with skin-restricted exposure amenable for topical use is of great interest. Systematic structure activity relationship study and multi-parameter optimization led to the discovery of a novel RORγ antagonist (SHR168442) with desired properties for a topical drug. It suppressed the transcription of IL-17 gene, leading to reduction of IL-17 cytokine secretion. It showed high exposure in skin, but low in plasma. Topical application of SHR168442 in Vaseline exhibited excellent efficacy in the imiquimod-induced and IL-23-induced psoriasis-like skin inflammation mouse models and correlated with the reduction of Th17 pathway cytokines, IL-6, TNFα and IL-17A. This work demonstrated restricted skin exposure of RORγ antagonist may provide a new topical treatment option as targeted therapeutics for mild to moderate psoriasis patients and may be suitable for the treatment of any other inflammatory disorders that are accessible locally.
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