JTE-151

Psoriasis is a chronic skin disease, and its symptoms markedly decrease patients' QOL. The detailed pathogenesis of psoriasis remains unclear, but previous reports about biologics targeting T helper type 17 (Th17)-related cytokines and autoantigens have suggested that both antigen- and cytokine-activated Th17 cells have important roles. Since retinoid-related orphan receptor-γ (RORγ) is recognized as the key master regulator of Th17 cells, we assessed the effects of pharmacological inhibition of RORγ using JTE-151, a novel orally available RORγ antagonist, on the activation of Th17 cells by antigen and cytokine. JTE-151 suppressed the production of both interleukin-17A (IL-17A) and IL-22 induced by myelin oligodendrocyte glycoprotein (35-55) peptide (MOG)-stimulated Th17 cells in vitro, whereas anti-IL-12/IL-23 p40 antibody did not. Moreover, JTE-151 also suppressed the production of both IL-17A and IL-22 induced by IL-23-stimulated Th17 cells in vitro. Furthermore, JTE-151 suppressed MOG-induced ear swelling in MOG-immunized mice and ameliorated IL-23-induced dermatitis in mice through the inhibition of Th17 cell activation. Taken together, we showed that pharmacological inhibition of RORγ by JTE-151 suppressed the activation of Th17 cells induced by both antigen and cytokine, and that it also ameliorated skin inflammation following Th17 cell activation. These results suggest that RORγ antagonists, including JTE-151, have the potential to become drug candidates for fighting psoriasis and other Th17-related autoimmune diseases, and that pharmacological inhibition of RORγ may also have broader effects than Th17-related cytokine-specific biological agents.

Retinoid-related orphan receptor-γ (RORγ) is a nuclear receptor that plays important roles in the development and activation of T helper type-17 (Th17) cells. In this study, we characterized the pharmacological profile of JTE-151 ((4S)-6-[(2-chloro-4-methylphenyl)amino]-4-{4-cyclopropyl-5-[cis-3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3yl}-6-oxohexanoic acid), which is a novel RORγ antagonist identified by our group. JTE-151 dissociated co-activator peptide from the human RORγ-ligand binding domain (LBD) and recruited co-repressor peptide into human RORγ-LBD, and potently inhibited the transcriptional activity of RORγ of human, mouse and rat. JTE-151 also demonstrated high selectivity against other receptors in nuclear receptor family. JTE-151 suppressed the differentiation of mouse naïve CD4⁺ T cells into Th17 cells without affecting the differentiation of those cells into other CD4⁺ T cell subsets in vitro. In addition, JTE-151 inhibited the production of interleukin-17 (IL-17) but not interferon-γ (IFN-γ) and IL-4 from activated human helper T cells in vitro. Furthermore, treatment with JTE-151 suppressed the production of IL-17 in antigen-sensitized mice and ameliorated the severity of arthritis in mice with collagen-induced arthritis regardless of treatment start date. Based on these results, we reasoned that JTE-151 could serve as a novel therapeutic compound for various autoimmune diseases linked to Th17 cells, such as psoriasis and rheumatoid arthritis.