Nuclear hormone receptors REV-ERBα and REV-ERBβ are ligand-activated transcription factors that control many physiological processes such as circadian clock regulation, inflammation, reproduction, development, and metabolism. The role of REV-ERBs in many physiological processes has created special interest for medicinal chemists to develop novel modulators with better selectivity and potency for treatment of a range of diseases including cancer, Alzheimer’s disease, autoimmune  diseases, and muscle regeneration. However, few REV-ERBα antagonists are available in the literature, and they suffer from poor pharmacokinetics. There is unmet need to develop chemical probes to understand the mechanism of action of ligand-binding to nuclear receptors and to develop drug candidates for diseases where REV-ERB plays significant role.<br/> <br/>Using Gaussian accelerated molecular dynamics (GaMD) simulations, and structure-based virtual ligand screening (VLS), we have recently identified potent and novel REV-ERBα antagonists. These studies led to identification of novel synthetic ligands bound to REV-ERBα  in an energetically favorable conformational state. Here in, we describe the synthesis and structure-activity relationships of our first-in-class REV-ERBα antagonists, and their biological evaluation.

Design and synthesis of the first-in-class REV-ERB antagonist for muscle regeneration

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

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