X-Ceptor Therapeutics, Inc.

Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1α as a strong coactivator of the orphan nuclear receptor estrogen-related receptor α (ERRα), implicating ERRα as a potential mediator of PGC-1α action. To understand the role of ERRα in PGC-1α signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERRα small-molecule regulators and target genes. We report here the identification of a potent and selective ERRα inverse agonist that interferes effectively with PGC-1α/ERRα-dependent signaling. This inverse agonist inhibits the constitutive activity of ERRα in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERRα target gene whose expression is regulated by PGC-1α and ERRα and inhibited by the ERRα inverse agonist. The discovery of potent and selective ERRα modulators and their effect on PGC-1α signaling provides mechanistic insight into gene regulation by PGC-1α. These findings validate ERRα as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.

Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression and play a critical role in endocrine signaling. Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function have not been completely elucidated. In recent years, the identification of natural ligands for these orphan receptors, their expression pattern in different tissues and studies with knock-out animals has delineated distinct regulatory functions for these proteins. The orphans belonging to the PPAR, LXR and FXR family function as lipid and bile-acid sensors while PXR and CAR function as xenobiotic sensors. This review will describe the discovery of natural and synthetic ligands for a number of these orphan receptors (excluding the PPARs) and the identification and characterization of novel signaling pathways and new hormone response systems linked to these targets. Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the Cyp3A gene, thereby playing a role in hepatoprotection and bile acid metabolism. A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics. The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.

The orphan nuclear receptors LXR, FXR and ERR function as ligand dependent transcription factors and serve as sensors for the regulation of lipid and energy metabolismTo elucidate the role of these receptors, we have identified potent, synthetic ligands in conjunction with transgenic and knockout animals to identify target genes for these receptors.The LXR modulators regulate key genes involved in the macrophage and the foam cell that control reverse cholesterol transport, as well as genes involved in inflammation.In animal models of atherosclerosis, LXR modulators increase reverse cholesterol transport and cause regression of atherosclerotic plaques.The regulation of LXR provides a novel approach to the treatment of atherosclerosis.Similar approaches have been employed for FXR and the ERRs in order to characterize their role as drug targets in cardiovascular and metabolic disorders.