Brent Lyda

Identification of SR2211: a potent synthetic RORγ-selective modulator.

Nuclear receptors (NRs) are ligand-regulated transcription factors that display canonical domain structure with highly conserved DNA-binding and ligand-binding domains. The identification of the endogenous ligands for several receptors remains elusive or is controversial, and thus these receptors are classified as orphans. One such orphan receptor is the retinoic acid receptor-related orphan receptor γ (RORγ). An isoform of RORγ, RORγt, has been shown to be essential for the expression of Interleukin 17 (IL-17) and the differentiation of Th17 cells. Th17 cells have been implicated in the pathology of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). Genetic ablation of RORγ alone or in combination with RORα in mice led to impaired Th17 differentiation and protected the mice from development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Here we describe SR2211, a selective RORγ modulator that potently inhibits production of IL-17 in cells.

Pharmacologic Repression of Retinoic Acid Receptor–Related Orphan Nuclear Receptor γ Is Therapeutic in the Collagen-Induced Arthritis Experimental Model

The nuclear receptor retinoic acid receptor–related orphan nuclear receptor γ (RORγ; T cell–specific isoform RORγt) is a key regulator of Th17 cell differentiation, controlling the production of the inflammatory cytokine interleukin‐17 (IL‐17). Lipopolysaccharide (LPS) stimulation of monocytes leads to the induction of RORγ. We previously showed that the potent and selective inverse agonist of RORγ, SR2211, was effective at suppressing IL‐17 production in EL4 cells. The aim of this study was to examine the effects of SR2211 treatment on proinflammatory cytokine expression in LPS‐stimulated RAW 264.7 cells as well as on joint inflammation in vivo in mice with collagen‐induced arthritis (CIA).

Synthetic modulators of the retinoic acid receptor-related orphan receptors

Nuclear receptors (NR) are ligand-regulated transcription factors that control the expression of target genes involved in a range of physiological processes such as development, metabolism, and immunity. The retinoic acid receptor-related orphan receptors alpha, beta, and gamma (RORA, RORB, and RORC) comprise a distinct subfamily of nuclear receptors and are considered ‘orphan’ receptors, as they have no known generally agreed upon endogenous ligands, although these receptors do bind to and are modulated by oxysterols. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands. The identification of potent and selective ROR ligands will allow for a better understanding of the roles of the ROR receptors in human disease, and potentially pave the way for development of novel therapeutics. Here we review the current status of synthetic ligand development from both the primary and patent literature.

Pharmacological repression of RORγ is therapeutic in the collagen-induced arthritis experimental model

The nuclear receptor retinoic acid receptor–related orphan nuclear receptor γ (RORγ; T cell–specific isoform RORγt) is a key regulator of Th17 cell differentiation, controlling the production of the inflammatory cytokine interleukin‐17 (IL‐17). Lipopolysaccharide (LPS) stimulation of monocytes leads to the induction of RORγ. We previously showed that the potent and selective inverse agonist of RORγ, SR2211, was effective at suppressing IL‐17 production in EL4 cells. The aim of this study was to examine the effects of SR2211 treatment on proinflammatory cytokine expression in LPS‐stimulated RAW 264.7 cells as well as on joint inflammation in vivo in mice with collagen‐induced arthritis (CIA).

Pharmacologic Repression of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γ Is Therapeutic in the Collagen-Induced Arthritis Experimental Model: Pharmacologic Repression of RORγ as Therapy for CIA

The nuclear receptor retinoic acid receptor–related orphan nuclear receptor γ (RORγ; T cell–specific isoform RORγt) is a key regulator of Th17 cell differentiation, controlling the production of the inflammatory cytokine interleukin‐17 (IL‐17). Lipopolysaccharide (LPS) stimulation of monocytes leads to the induction of RORγ. We previously showed that the potent and selective inverse agonist of RORγ, SR2211, was effective at suppressing IL‐17 production in EL4 cells. The aim of this study was to examine the effects of SR2211 treatment on proinflammatory cytokine expression in LPS‐stimulated RAW 264.7 cells as well as on joint inflammation in vivo in mice with collagen‐induced arthritis (CIA).