Alzheimer’s disease is a neurodegenerative dementia that affects about 47 million patients worldwide and has been identified as the sixth-leading cause of death in the United States. There are large unmet needs in the field of drug development of therapeutics for AD.<br/>Estrogen related receptors are members of the nuclear hormone receptors superfamily, which are ligand-activated transcription factors. Ligands of nuclear receptors tend to activate or repress the transcription factors that control several genes involved in physiological processes such as metabolism, immunity, inflammation, homeostasis, development, cell growth, and reproduction.<br/>The estrogen related receptors subfamily comprise three members, ERRα, ERRβ and ERRγ. They are closely related to the estrogen receptors but unlike ER receptors, they have constitutive activity and can function in absence of ligands.<br/>ERRα is expressed mainly in tissues of high energy demand such as brown adipose tissue, intestine, skeletal muscles, and brain and functions as a sensor of energy metabolism. There is a growing evidence that ERRα is a potential drug target in Alzheimer’s Disease (AD) because of the role it plays in regulating genes involved in oxidative stress and because of its anti-inflammatory properties. Recently, overexpression of ERRα was shown to inhibit the processing of β-amyloid precursor protein (APP) and reduce phosphorylation of Tau in HEK/APP cells, both under normal conditions and under oxidative stress. ERRα is regulated by energy status in the brain and clinical dementia is strongly associated with attenuation in energy metabolism. Therefore, ERRα could also play role in the pathology of dementia.<br/>ERRα is known to be highly intractable as a drug target. The progress in drug development for ERRα is limited to the development of inverse agonists. We have identified ERRα agonists and developing these agonists to be used as chemical probes to validate ERRα as a putative target for the treatment of Alzheimer’s disease.

Structure-based design of estrogen related receptor α agonists for treatment of Alzheimer's disease

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.