Inhibition of RORγt activity and Th17 differentiation by a set of novel compounds

Retinoic acid receptor-related orphan receptor gamma t (RORγt) is the master regulator of Th17 cell differentiation, which plays a critical role in the pathology of several autoimmune diseases. By directing Th17 cells function, RORγt could be a potential target for drug development for Th17 related autoimmune disease.

A Jurkat cell-based reporter assay system was used for screening RORγt inhibitors from a drug-like chemical library, following with mouse Th17 cells differentiation study to identify the effect of targeted compounds in primary T cells. 293T cell-based reporter assay was conducted to determine the cell specificity, and MTT assay was performed to determine the cell toxicity of those compounds.

In this study, we identified four lead compounds that suppressed RORγt activity, Th17 differentiation and IL-17A secretion. These candidates displayed inhibition ability on RORγt activity in T cell derived Jurkat cell, but not in 293 T cell, which indicated the restricted effects of these compounds to other cells or tissues. Futhermore, our results demonstrated that these candidates exhibited more robust inhibitory on IL-17 F transcription expression than IL-17A, which is different from one reported compound, SR1001, that mainly suppressed IL-17A, rather than IL-17 F production.

Our study discovered four novel compounds that inhibited RORγt activity and Th17 function, which indicates their potential in therapeutic application of Th17 related autoimmune disorders.