Retinoic Acid Receptor (RAR)-Related Orphan Receptors RORα, RORγ and RORγt are key transcription factors required for differentiation of naive CD4+ helper cells into Th17 cells that play an important role in driving autoimmune and inflammatory diseases by secretion of IL-17 and other pro-inflammatory cytokines. Recently development of the Th17 immunomodulators as potential therapeutics for autoimmune diseases has been focused on ROR proteins to regulate differentiation and IL-17 production of Th17 cells. We designed a small molecule compound VPR-66 via the molecular modeling study, which is hypothesized to bind to the ligand-binding domain (LBD) of ROR proteins. VPR-66 was characterized by two different cell-based reporter assays, in which the LBD or full-length of ROR proteins were utilized. In the LBD-based assay, VPR-66 selectively suppressed the RORα and RORγt LBD-mediated transcriptional activity but showed little or no effects on VP16 control protein- or RARα LBD-mediated transcriptional activity. Similarly, in the full-length ROR-based assay, VPR-66 significantly inhibited RORγ- or RORγt-induced IL-17A promoter activity while VPR-66 did not affect the promoter activity in the absence of ROR protein expression. Taken together, it is proposed that VPR-66 acts as an inverse agonist specific for ROR proteins and its binding to ROR proteins interferes with transcriptional complex formation for IL-17 induction.
- Copyright © 2013 by The American Association of Immunologists, Inc.