Research Terms
These potent anti-inflammatory compounds have been designed to treat inflammatory conditions but with reduced, serious side effects associated with the long-term use of traditional glucocorticoid drugs. Glucocorticoids are one of the most prescribed drug classes due to their remarkable anti-inflammatory properties and are used to treat acute and chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and atopic dermatitis. But, despite their efficacy and broad therapeutic spectrum, undesired negative side effects restrict long-term systemic and local treatments with the currently available glucocorticoid drugs.
Chronic treatment with glucocorticoids can induce insulin resistance, leading to reduced glucose uptake in the primary organ for glucose disposal, the skeletal muscle, facilitating muscle wasting. These side effects are due to decreased protein synthesis and increased protein degradation, leading to cachexia and, muscle atrophy. They also cause growth retardation in children, osteoporosis, and skin effects, including skin thinning and impaired wound healing. An incomplete understanding of the molecular mechanisms through which glucocorticoids mediate activity via the glucocorticoid receptor has impaired efforts to develop improved glucocorticoids. There is a need for dissociated glucocorticoid compounds with improved therapeutic activity and reduced undesirable side effects.
Researchers at the University of Florida have identified two rationally developed anti-inflammatory compounds, SR16024 and SR11466. Both novel molecules act through the glucocorticoid receptor, but in animal models show reduced side effects associated with long-term use of glucocorticoids. The compounds possess dissociated activity, enabling the treatment of inflammatory diseases without negatively impacting muscle mass and with improved effects on osteoblast mineralization and glucose disposal. These novel anti-inflammatory agents can potentially replace existing drugs such as cortisone, hydrocortisone, and prednisone.
New glucocorticoid compounds for treating inflammatory conditions, but with reduced, negative side effects, including Duchenne muscular dystrophy
These two new glucocorticoids, SR16024 and SR11466, potentially enable the treatment of inflammatory and autoimmune conditions without leading to undesired side effects, such as muscle wasting and cachexia. Glucocorticoids exert their effects by binding and activating the glucocorticoid receptor. Additionally, the compounds present the potential for treating and ameliorating symptoms of Duchenne muscular dystrophy, for which glucocorticoids are the only treatment, but lead to growth retardation and bone fractures.
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.
Small-molecule REV-ERBα agonists for the treatment of TH17-mediated autoimmunity, inflammatory disorders, and cancer
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.
