Modulation of estrogen-related receptors subtype selectivity: Conversion of an ERRβ/γ selective agonist to ERRα/β/γ pan agonists.

ABSTRACT: Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα.

SUBMITTER: Shahien M 

PROVIDER: S-EPMC9137328 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature