RTA 1701 is an orally-bioavailable, potent, and selective RORγt inhibitor that suppresses Th17 differentiation in vitro and is efficacious in mouse models of autoimmune disease.

Abstract

Abstract Retinoic acid-related orphan receptor γt (RORγt) is a transcription factor that directs the differentiation of Th17 cells, a subset of CD4+ helper T cells involved in autoimmune disorders. Once differentiated, Th17 cells secrete interleukin-17A (IL-17A) and other key cytokines implicated in autoimmune and inflammatory disease. Antibodies that target Th17 cells are approved for several autoimmune disorders, validating the important role of Th17 cells in disease. RTA 1701 is a potent and selective RORγt inhibitor in preclinical development for autoimmune disorders. It inhibits the activity of RORγt, as assessed using ligand binding domain and full-length RORγt reporters. Moreover, RTA 1701 is selective for RORγt and does not inhibit the activity of two closely-related receptors, RORα and RORβ. By inhibiting RORγt, RTA 1701 blocks Th17 differentiation of naïve CD4+ T cells and IL-17A production by both Th17 polarized CD4+ T cells and activated peripheral blood mononuclear cells (PBMCs). The expression of other RORγt target genes and Th17 signature genes (eg, IL-17F, IL-21, CCL20) is also reduced following RTA 1701 treatment of Th17-polarized naïve CD4+ T cells, as assessed by qPCR. RTA 1701 is orally bioavailable with excellent pharmacokinetic properties in rodents and monkey. Furthermore, this compound is efficacious in animal models of autoimmune disease, including the collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis and the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Together, these results suggest that RORγt inhibition by RTA 1701 may have therapeutic potential in Th17-associated autoimmune disorders.