REV-ERB and ROR nuclear receptors as drug targets

Key Points The nuclear receptors retinoic acid receptor-related orphan receptor-α (RORα), RORβ, RORγ, REV-ERBα and REV-ERBβ were originally identified as orphan receptors. RORα and RORβ constitutively activate transcription, whereas REV-ERBα and REV-ERBβ constitutively silence transcription. RORα and RORγ are now known to bind to sterols, with certain oxysterols having a very high affinity for these receptors. REV-ERBs have been found to bind to haem. REV-ERBs function as ligand-dependent (that is, haem-dependent) silencers of transcription. The role of the endogenous ligands for the RORs is less clear, as several sterols and oxysterols have been suggested to function as agonists or inverse agonists. The RORs and REV-ERBs have substantially overlapping functions as they usually recognize similar DNA response elements. These receptors have important roles in many physiological functions, including development, circadian rhythm, metabolism and immune function. Over the past several years, synthetic ligands have been designed that target RORs and REV-ERBs. Many of these have high potency and have been used to examine the utility of targeting RORs and REV-ERBs in animal models of human disease. Synthetic REV-ERB agonists alter the circadian rhythm and have beneficial effects on the metabolic profile in obese mice. REV-ERB agonists increase oxidative metabolism in the skeletal muscle and improve exercise endurance in mice. Synthetic inverse agonists of ROR (that either target RORγ alone or both RORα and RORγ) are effective in treating and preventing autoimmunity in mouse models. Additionally, they have beneficial effects on glucose and lipid metabolism. The continued refinement and development of synthetic ligands that target these former orphan nuclear receptors may yield novel therapeutics to treat a range of diseases in the future. This Review highlights recent progress in the development of ligands to target two classes of nuclear receptors — the REV-ERBs and retinoic acid receptor-related orphan receptors (RORs) — and describes how such ligands might be useful for treating disorders related to metabolism, immune function and the circadian rhythm. The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent ch