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 (T_H17 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 (K_is = 172 and 111 nM, respectively) that functions as an inverse agonist at these receptors.¹ 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 T_H17 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.¹

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1. Solt, L.A., Kumar, N., Nuhant, P., et al. Suppression of T_H17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472(7344), 491-494 (2011).