The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist

Retinoic acid receptor-related orphan receptors (RORs) regulate a variety of physiological processes including hepatic gluconeogenesis, lipid metabolism, circadian rhythm, and immune function. Here we present the first high-affinity synthetic ligand for both RORα and RORγ. In a screen against all 48 human nuclear receptors, the benzenesulfonamide liver X receptor (LXR) agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317) inhibited transactivation activity of RORα and RORγ but not RORβ. T0901317 was found to directly bind to RORα and RORγ with high affinity (Ki = 132 and 51 nM, respectively), resulting in the modulation of the receptor's ability to interact with transcriptional cofactor proteins. T0901317 repressed RORα/γ-dependent transactivation of ROR-responsive reporter genes and in HepG2 cells reduced recruitment of steroid receptor coactivator-2 by RORα at an endogenous ROR target gene (G6Pase). Using small interference RNA, we demonstrate that repression of the gluconeogenic enzyme glucose-6-phosphatase in HepG2 cells by T0901317 is ROR-dependent and is not due to the compound's LXR activity. In summary, T0901317 represents a novel chemical probe to examine RORα/γ function and an excellent starting point for the development of ROR selective modulators. More importantly, our results demonstrate that small molecules can be used to target the RORs for therapeutic intervention in metabolic and immune disorders

Suppression of TH17 Differentiation and Autoimmunity by a Synthetic ROR Ligand

T helper cells that produce Interleukin-17 (IL-17) (TH17 cells) are a recently identified CD4+T-cell subset with characterized pathological roles in autoimmune diseases1–3. The nuclear receptors retinoic acid receptor-related orphan receptors α and γt (RORα and RORγt) have indispensible roles in the development of this cell type4–7. Here we present a first-in-class, high-affinity synthetic ligand, SR1001, specific to both RORα and RORγt that inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand binding domains (LBDs) of RORα and RORγt inducing a conformational change within the LBD that encompasses repositioning of helix 12 leading to diminished affinity for coactivators and increased affinity for corepressors resulting in suppression of the receptors transcriptional activity. SR1001 inhibited the development of murine TH17 cells as demonstrated by inhibition of IL-17A gene expression and protein production. Additionally, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Thus, our data demonstrates the feasibility of targeting the orphan receptors RORα and RORγt to specifically inhibit TH17 cell differentiation and function and indicates that this novel class of compound has potential utility in the treatment of autoimmune diseases