Small molecule mediated inhibition of RORγ‐dependent gene expression and autoimmune disease pathology in vivo
Retinoic acid receptor‐related orphan nuclear receptor γ (RORγ) orchestrates a pro‐inflammatory gene expression programme in multiple lymphocyte lineages including T helper type 17 (Th17) 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 Th17 cells, where RORγ expression is induced under specific pro‐inflammatory conditions, γδ T cells and other innate‐like immune cells express RORγ in the steady state. Small molecule mediated disruption of RORγ function in cells with pre‐existing RORγ transcriptional complexes represents a significant and challenging pharmacological hurdle. We present data demonstrating that a novel, selective and potent small molecule RORγ inhibitor can block the RORγ‐dependent gene expression programme in both Th17 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.
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