Pharmacological Evaluation of TAK-828F, a Novel Orally Available RORγt Inverse Agonist, on Murine Colitis Model
IL-17-producing Th17 cells and IFN-γ and IL-17 double-producing Th1/17 cells have been identified as the pathogenic cells in inflammatory bowel disease (IBD). Retinoic acid-related orphan receptor γt (RORγt) is a master regulator for the differentiation and activation of Th17 and Th1/17 cells. We discovered a novel orally available TAK-828F, a strong and selective RORγt inverse agonist. To assess the potential of RORγt blockade in the therapy for IBD, the efficacy of TAK-828F in activated T cell transfer mouse colitis model was investigated. This model was highly sensitive to the prophylactic treatment of anti-TNF-α monoclonal antibody but partially susceptible to sulfasalazine, tacrolimus, and prednisolone. Oral administration of TAK-828F, at doses of 1 and 3 mg/kg, b.i.d, strongly protected the progression of colitis. TAK-828F decreased the population of Th17 and Th1/17 cells in a dose-dependent manner in the mesenteric lymph node. Moreover, expression of mRNA that are characteristic of the Th17 signature, such as IL-17A and IL-17F in the colon, were inhibited by TAK-828F, while the expression of IL-10, an anti-inflammatory cytokine, was increased. In the therapeutic treatment, TAK-828F lessened disease severity compared to the vehicle control mice. Interestingly, gene expression of zonula occludens-1 (ZO-1) and mucin 2 (Muc2), which play an important role in barrier function of the intestinal mucosa, was recovered by TAK-828F. These results indicate that blocking RORγt has promising pharmacological profile in the colitis model. RORγt blockade may provide a novel therapeutic paradigm for treatment of IBD with unique mechanism by which improves imbalance of the immune system.
Publisher URL: https://link.springer.com/article/10.1007/s10753-018-0875-7