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

Retinoic acid receptor-related orphan nuclear receptor gamma (ROR gamma) orchestrates a pro-inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) cells, gamma delta T cells, innate lymphoid cells and lymphoid tissue inducer cells. There is compelling evidence that ROR gamma-expressing cells are relevant targets for therapeutic intervention in the treatment of autoimmune and inflammatory diseases. Unlike Th17 cells, where ROR gamma expression is induced under specific pro-inflammatory conditions, gamma delta T cells and other innate-like immune cells express ROR gamma in the steady state. Small molecule mediated disruption of ROR gamma function in cells with pre-existing RORc transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule ROR gamma inhibitor can block the ROR gamma-dependent gene expression programme in both Th17 cells and ROR gamma-expressing gamma delta T cells as well as a disease-relevant subset of human ROR gamma-expressing memory T cells. Importantly, systemic administration of this inhibitor in vivo limits pathology in an innate lymphocyte-driven mouse model of psoriasis.