Pharmacological inhibition of ROR gamma t suppresses the Th17 pathway and alleviates antigen-induced arthritis in-vivo

Retinoic acid receptor-related-orphan-receptor-C (ROR gammat) is the key transcription factor that is driving the differentiation of IL-17 producing T-helper 17 (Th17) cells that are implicated in the pathology of various autoimmune and inflammatory diseases. Based on the importance of RORgammat in promoting Th17-driven pathology, there is considerable interest to develop low-molecular-weight compounds with the aim to inhibit the transcriptional activity of this nuclear hormone receptor. In this article, we describe the in-vitro and in-vivo pharmacology of a potent and selective small-molecular-weight RORgammat inverse agonist. The compound binds to the ligand binding domain (LBD) of RORgammat leading to displacement of a co-activator peptide. We show for the first time that a RORgammat inverse agonist down-regulates permissive histone H3 acetylation and methylation at the IL17A and IL23R promoter regions, thereby providing insight into the transcriptional inhibition of RORgammat-dependent genes. Consitent with this, the compound effectively reduced IL-17A production by polarized human gamma delta T-cells and by T-cells and attenuated transcription of RORgammat target genes. The inhibitor showed good in-vivo efficacy in an antigen-induced arthritis model in rats and reduced the frequencies of IL-17A producing cells in ex-vivo recall assays. In summary, we demonstrate that inhibiting RORgammat by a low-molecular-weight inhibitor results in efficient and selective blockade of the pro-inflammatory Th17/IL-17A pathway making it an attractive target for Th17-mediated disorders.