SR 1001

Retinoic-acid-receptor-related orphan receptors (ROR) α and γ play a key role in the development of T-helper cells that produce interleukin-17 (TH17 cells), a subset of CD4+ T-cells that contribute to the inflammatory process and have been implicated in the pathology of autoimmune diseases. SR 1001 is a synthetic ligand specific for RORα and RORγ (Kis = 172 and 111 nM, respectively) that functions as an inverse agonist at these receptors. SR 1001 has been shown to suppress IL-17 promoter driven transcriptional activity by inhibiting the interaction of co-activators such as TRAP220 nuclear receptor box 2 peptide (IC50 = 117 nM) and SRC2 with RORα and RORγ as well as by increasing the recruitment of corepressors such as NCoR. At 5 μM, SR 1001 inhibits TH17 cell differentiation and IL-17A secretion in cultured splenocytes and human PBMCs. A 25 mg/kg dose of SR 1001 twice/day delays the onset and the severity of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis.