Small molecule mediated inhibition of RORγ-dependent gene expression and autoimmune disease pathology in vivo.

Abstract The orphan nuclear receptor RORγ orchestrates a pro-inflammatory gene expression program in multiple lymphocyte lineages including Th 17 helper T cells, γδ T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that RORγ-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th 17 cells, where RORγ expression is induced under specific proinflammatory conditions, γδT cells and other innate like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with preexisting RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. Here we present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ-dependent gene expression program in both Th 17 cells and RORγ-expressing γδ T cells as well as a disease relevant subset of human RORγ-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte driven mouse model of psoriasis. This article is protected by copyright. All rights reserved.