SR 1001

SR1001 is a selective RORα and RORγ inverse agonist; inhibits TH17 cell differentiation and function.

In Vitro:SR1001 inhibits the development of murine TH17 cells by inhibition of IL-17A gene expression and protein production. SR1001 reduces the interaction of a coactivator TRAP220 NR box 2 peptide with RORγ in a dose dependent manner (IC50 value≈117 nM). Additionally, SR1001 inhibits the expression of cytokines when added to differentiated murine or human TH17 cells[1].

In Vivo:SR1001 effectively suppresses the clinical severity of autoimmune disease in mice. Administration of SR1001 to C57BL/6 mice suppresses the expression of hepatic ROR target genes, Cyp7b1, Rev-erbα, and Serpine 1[1]. SR1001 a RORα inverse agonist eliminats the circadian pattern of expression of citrate synthase mRNA in mice[2].

References:
[1]. Solt LA, et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature. 2011 Apr 28;472(7344):491-4. [2]. Crumbley C, et al. Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor α (RORα). PLoS One. 2012;7(4):e33804.

Inflammatory T helper 17 cells promote depression-like behavior in mice.[Pubmed:23174342]

Biol Psychiatry. 2013 Apr 1;73(7):622-30.

BACKGROUND: Recognition of substantial immune-neural interactions is revising dogmas about their insular actions and revealing that immune-neural interactions can substantially impact central nervous system functions. The inflammatory cytokine interleukin-6 promotes susceptibility to depression and drives production of inflammatory T helper 17 (Th17) T cells, raising the hypothesis that in mouse models, Th17 cells promote susceptibility to depression-like behaviors. METHODS: Behavioral characteristics were measured in male mice administered Th17 cells, CD4(+) cells, or vehicle and in retinoid-related orphan receptor-gammaT (RORgammaT)(+/GFP) mice or male mice treated with RORgammaT inhibitor or anti-interleukin-17A antibodies. RESULTS: Mouse brain Th17 cells were elevated by learned helplessness and chronic restraint stress, two common depression-like models. Th17 cell administration promoted learned helplessness in 89% of mice in a paradigm where no vehicle-treated mice developed learned helplessness, and impaired novelty suppressed feeding and social interaction behaviors. Mice deficient in the RORgammaT transcription factor necessary for Th17 cell production exhibited resistance to learned helplessness, identifying modulation of RORgammaT as a potential intervention. Treatment with the RORgammaT inhibitor SR1001, or anti-interleukin-17A antibodies to abrogate Th17 cell function, reduced Th17-dependent learned helplessness. CONCLUSIONS: These findings indicate that Th17 cells are increased in the brain during depression-like states, promote depression-like behaviors in mice, and specifically inhibiting the production or function of Th17 cells reduces vulnerability to depression-like behavior, suggesting antidepressant effects may be attained by targeting Th17 cells.

Regulation of expression of citrate synthase by the retinoic acid receptor-related orphan receptor alpha (RORalpha).[Pubmed:22485150]

PLoS One. 2012;7(4):e33804.

The retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily of transcription factors that plays an important role in regulation of the circadian rhythm and metabolism. Mice lacking a functional RORalpha display a range of metabolic abnormalities including decreased serum cholesterol and plasma triglycerides. Citrate synthase (CS) is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, CS plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis. Here, we identified a functional RORalpha response element (RORE) in the promoter of the CS gene. ChIP analysis demonstrates RORalpha occupancy of the CS promoter and a putative RORE binds to RORalpha effectively in an electrophoretic mobility shift assay and confers RORalpha responsiveness to a reporter gene in a cotransfection assay. We also observed a decrease in CS gene expression and CS enzymatic activity in the staggerer mouse, which has a mutation of in the Rora gene resulting in nonfunctional RORalpha protein. Furthermore, we found that SR1001 a RORalpha inverse agonist eliminated the circadian pattern of expression of CS mRNA in mice. These data suggest that CS is a direct RORalpha target gene and one mechanism by which RORalpha regulates lipid metabolism is via regulation of CS expression.

Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.[Pubmed:21499262]

Nature. 2011 Apr 28;472(7344):491-4.

T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gammat (RORalpha and RORgammat, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORalpha and RORgammat and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORalpha and RORgammat, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORalpha and RORgammat to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.