Retinoic Acid-related Orphan Receptors in Drug Discovery

Retinoic Acid Receptor-Related Orphan Receptor Gamma (RORγ)

What is the Retinoic Acid Receptor-Related Orphan Receptor Gamma (RORγ)?

The Retinoic Acid Receptor-Related Orphan Receptor Gamma (RORγ or RORC) is an intracellular transcription factor that is part of the nuclear hormone receptor family. RORγ is one of the three forms of ROR in addition to RORα and RORβ. Each is encoded by a separate gene, RORA, RORB, and RORC respectively. The RORs are a unique set of receptors in that they bind as monomers to hormone response elements, as opposed to the majority of other nuclear receptors which bind as dimers. They bind to DNA elements called ROR response elements (RORE). RORs are activated by oxysterols and may function as lipid sensors and hence may play a role in the regulation of lipid metabolism. RORγ is activated by multiple endogenous ligands and controls the expression of genes involved in immune cell differentiation and function.

RORγ’s Role in Disease and T-helper 17 Cells

RORγ is known to activate transcription through ligand-dependent interactions with co-regulators and is involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. RORγ plays a critical role in the differentiation and function of immune cells, including T-helper 17 (Th17) cells. Th17 cells produce pro-inflammatory cytokines, such as interleukin-17 (IL-17), which contribute to tissue inflammation and damage in diseases like psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Inhibition of RORγ activity by inverse agonists has been shown to reduce the production of pro-inflammatory cytokines and alleviate disease symptoms in animal models of autoimmune diseases. RORγ has several isoforms, including RORγt, which is specifically expressed in Th17 cells and plays a critical role in Th17 cell differentiation and function. RORγt is essential for the development of Th17 cells, and its genetic deletion or inhibition has been shown to reduce Th17 cell differentiation and disease severity in animal models of autoimmune diseases.

Research on RORs contributing to cancer-related processes has been increasing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers. For example, RORα has been identified as a potential therapeutic target for breast cancer and has been investigated in melanoma, colorectal colon cancer, and gastric cancer. RORβ is mainly expressed in the central nervous system, but it has also been studied in pharyngeal cancer, uterine leiomyosarcoma, and colorectal cancer, in addition to neuroblastoma. Recent studies suggest that RORγ is involved in various cancers, including lymphoma, melanoma, and lung cancer. In addition, some studies found RORγ to be upregulated in cancer tissues compared with normal tissues, while others indicated the opposite results. With respect to the mechanisms of RORs in cancer, previous studies on the regulatory mechanisms of RORs in cancer were mostly focused on immune cells and cytokines, but lately there have been investigations concentrating on RORs themselves.

RORγ’s Role in Drug Discovery

RORγ has been implicated in several autoimmune diseases, including multiple sclerosis and inflammatory bowel disease. Several synthetic compounds that activate or inhibit RORγ are currently being developed and tested as potential drug candidates. One example is VTP-43742, a small molecule RORγt inhibitor that is being developed for the treatment of psoriasis and other autoimmune diseases. VTP-43742 has shown promising results in preclinical models, with a favorable safety and pharmacokinetic profile. Another example is SR1001, a selective RORγt inverse agonist that is being investigated for the treatment of inflammatory bowel disease. SR1001 has shown efficacy in preclinical models, and a phase II clinical trial has demonstrated its safety and tolerability in human subjects. Several natural compounds, such as melatonin and honokiol, have also been shown to modulate RORγ activity and are being investigated as potential drug candidates for various indications, including inflammation and cancer. The development of RORγ-targeted drugs is an active area of research and holds great promise for the treatment of various immune-mediated diseases.

INDIGO’s RORγ Reporter Assays

INDIGO’s RAR-related Orphan Receptor Gamma (RORγ) assay kit is an all-inclusive firefly luciferase reporter assay system that includes, in addition to RORγ Reporter Cells, two optimized media for use during cell culture and (optionally) in diluting the test samples, a reference inverse-agonist, Luciferase Detection Reagent, a cell culture-ready assay plate, and a detailed protocol.

INDIGO’s cell-based reporter assays allow scientists to detect any biological activity that their test samples may exert against a specific receptor present in the cell. They utilize firefly luciferase reporter gene technology which provides superior precision and sensitivity. Since the receptor binding controls the expression of the luciferase reporter gene, luciferase activity in the cells can be correlated directly with the activity of the receptor. The strength of an interaction of a chemical with the target receptor is quantified using a luminometer to measure the level of light emitted. Learn more about INDIGO’s INDIGlo Luciferase Detection Reagent Kits.


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