Retinoic acid receptor-related orphan receptors (RORs) are ligand-dependent transcriptional factors and members of the nuclear receptor superfamily. In fact, RORs regulate inflammation, metabolic disorders, and circadian rhythm. RORs include RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). Of these, RORα is a potential therapeutic target for breast cancer, melanoma, colorectal colon cancer, and gastric cancer. RORβ mainly expresses in the central nervous system. Typically, RORγ is a promising therapeutic drug target for treating Th17-mediated autoimmune diseases. In particular, RORγ is essential for Interleukin 17 (IL-17) expression and the differentiation of Th17 cells. Especially, Th17 cells implicated in the pathology of several autoimmune diseases including multiple sclerosis (MS) and rheumatoid arthritis (RA).

Here, Naresh Kumar, et al describe SR2211, a selective RORγ modulator that potently inhibits the production of IL-17 in cells. Importantly, SR2211 can bind RORγ and displace radioligand [3H]T1317 in a competition based SPA assay. The calculated Ki value for SR2211 is 105 nM. To further evaluate the nature of the interaction of SR2211 with RORγ, researchers performed differential hydrogen/deuterium exchange (HDX) mass spectrometry analysis of the RORγ LBD in the presence and absence of digoxin, T1317, or SR2211. SR2211 treatment dies not have any impact on the transcriptional activity of RORα, whereas more than 95% inhibition of RORγ activity was observed at 10 M. Moreover, SR2211 modulates full-length RORγ in reporter assays. Besides, SR2211 significantly represses the 5X-RORE luciferase activity when full-length RORγ is added during transfection. Furthermore, SR2211 can inhibit the transcriptional activity of RORγ resulting in the suppression of IL-17 production.

To summarise, SR2211 is a potent and specific RORγ inverse agonist, which has potential utility for the treatment of inflammatory disease.

Kumar N, et al. Identification of SR2211: a potent synthetic RORγ-selective modulator. ACS Chem Biol. 2012 Apr 20;7(4):672-7.