The retinoic acid-related orphan receptor (ROR) isoforms RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3) are members of the steroid nuclear hormone receptor superfamily. RORs play prominent roles in a variety of biological processes including organ development, immunity, lipid homeostasis and metabolism, and circadian rhythm. RORγt is also critical for the development of lymph nodes and Peyer’s patches and for the differentiation of thymocytes. Furthermore, RORγt is the obligatory transcription factor. It controls the differentiation of naive CD4+ T cells into Th17 lineage. Meanwhile, it regulates transcription of the effector cytokine IL17 in Th17 cells and cells of the innate immune response in both rodents and humans. In this study, A-9758 is a RORγ ligand and a potent, selective RORγt inverse agonist. It exhibits robust potency against IL-17A release.
A-9758 is a RORγ ligand and a potent, selective RORγt inverse agonist. It exhibits robust potency against IL-17A release.
A-9758 inhibits, in a concentration-dependent manner, human RORγ transactivation with an IC50 of 38 nM. In addition, A-9758 also inhibits mouse RORγ transactivation with similar activity. Meanwhile, it is equally active on dog and rat RORγ (25 and 64 nM, respectively). A-9758 is selective for ROR family. It is approximately 14 fold specific for RORγt (IC50=5 nM) over RORα and nearly 270 fold specific over RORβ. Moreover, A-9758 inhibits binding of the co-activators PGC1a and NCoA1 and conversely increases binding of the co-repressors NCoR1 and NCoR2. A-9758 inhibits IL-17A produced by stimulated human CD4+ and mouse splenocytes.
In vivo, A-9758 results in a 78±5% reduction in systemic IL-17A levels driven by MOG/anti-CD3 challenge. A-9758 is effective in robustly blocking the production of IL-17F and to a lesser extent IL-22. A-9758 is effective in reducing ear inflammation driven by IL-23 in a dose dependent manner and with a robust exposure-efficacy relationship. In a word, in the IL-23 model of psoriasiform dermatitis and GPI-model of arthritis, A-9758 was effective in attenuating further disease progression at the tissue (ear or paw thickness) or mechanistic level (decreased IL-17A production).
All in all, A-9758 is a potent, selective RORγt inverse agonist. It significantly attenuates IL-23 driven psoriasiform dermatitis and is effective in blocking skin and joint inflammation.