Activates the REV-ERBα Nuclear Receptor to Suppress TH17 Cell Development and TH17-Mediated Autoimmune and Chronic Inflammation
These small molecules activate the REV-ERBα nuclear receptor to repress TH17 cell activity and treat autoimmune and chronic inflammatory disorders. TH17 cells are a subset of CD4+ T cells that play key roles in protective immunity under homeostatic conditions. However, impaired TH17 cell homeostasis can lead to various disease states. In these conditions, TH17 cells often contribute to the pathogenesis of numerous autoimmune diseases, such as multiple sclerosis and psoriasis. Multiple studies have identified the nuclear receptors RORγt and the REV-ERBs (REV-ERBα and REV-ERBβ) as main drivers or inhibitors of TH17 cell development and pathogenicity, respectively, often co-regulating the same target genes. The main difference between them is that while RORγt is an activator of gene transcription, the REV-ERBs behave as repressors. Although numerous RORγt inhibitors have entered clinical trials for the treatment of various autoimmune diseases, most have been discontinued or withdrawn due to toxic and carcinogenic side effects, such as an increase in the risk of developing thymic lymphoma. Conversely, REV-ERBα activity is essential for reducing TH17-mediated pro-inflammatory cytokine expression. Its pharmacological activation has shown promise in improving some inflammatory conditions such as allergic inflammation, asthma or non-alcoholic steatohepatitis. REV-ERBα agonists also have demonstrated efficacy in treating metabolic disorders. Additionally, REV-ERBα activation can effectively impair oncogenic processes, making REV-ERBα agonists a potentially effective therapeutic option against different types of cancers, highlighting their broad therapeutic potential.
Researchers at the University of Florida have synthesized small-molecule REV-ERBα agonists for the treatment of autoimmune, inflammatory diseases, and cancer. By targeting and activating the REV-ERBα receptor, they can inhibit TH17 cell differentiation and TH17-mediated disorders.
Application
Small-molecule REV-ERBα agonists for the treatment of TH17-mediated autoimmunity, inflammatory disorders, and cancer
Advantages
- Small molecules bind to REV-ERBα instead of RORγt to suppress TH17 cells, circumventing safety issues associated with RORγt modulators
- Administration routes include oral, topical and inhalation, eliminating the need for injectable therapeutics
Technology
TH17 cells play an important role in tissue homeostasis and protective immunity. However, they are also involved in the pathogenesis of multiple autoimmune diseases, such as multiple sclerosis, psoriasis, and inflammatory bowel diseases. Available therapies focus on targeting and inhibiting the lineage defining transcription factor for TH17 cells, the nuclear receptor RORγt. However, these RORγt-selective therapeutics carry serious safety concerns, such as liver toxicity and the risk for developing thymic lymphoma. Researchers at the University of Florida have synthesized small molecules targeting another nuclear receptor, REV-ERBα. Since the presence of REV-ERBα negatively regulates pro-inflammatory TH17 cell responses, the inventors have designed these small molecules to act as agonists of REV-ERBα. By binding to and activating the REV-ERBα receptor, they can suppress TH17 cell differentiation and maturation to ultimately treat TH17 cell-mediated disorders. These compounds have shown efficacy in preclinical models of autoimmune diseases, demonstrating their potential for clinical application.
Brochure
