Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available ROR gamma t inverse agonist

Retinoic acid-related orphan receptor gamma t (ROR gamma t) is a key master regulator of the differentiation and activation of IL-17 producing CD4(+) Th17, CD8(+) Tc17 and IL-17/IFN-gamma co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, ROR gamma t is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective ROR gamma t inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01-10 mu M without affecting the production of IFN-gamma. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells' differentiation from naive T cells and memory CD4(+) T cells at 100 nM without affecting Th1 cells' differentiation. In addition, TAK-828F improved Th17/Treg cells' population ratio by inhibiting Th17 cells' differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-gamma production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against ROR gamma t both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells' differentiation and improving imbalance between Th17 and Treg cells.