2. Academic Validation
  3. Discovery of BE2012, a First-in-Class REV-ERBα/β Antagonist with Favorable Selectivity and Pharmacokinetics, and In Vivo Efficacy in Inducing Key Myogenic Factors for Muscle Repair upon Acute Muscle Injury

Discovery of BE2012, a First-in-Class REV-ERBα/β Antagonist with Favorable Selectivity and Pharmacokinetics, and In Vivo Efficacy in Inducing Key Myogenic Factors for Muscle Repair upon Acute Muscle Injury

  • J Med Chem. 2026 Jan 8;69(1):439-465. doi: 10.1021/acs.jmedchem.5c02749.
Lingaiah Maram 1 2 3,  Aurore-Cecile Valfort 4,  Mohammad Homaidur Rahman 2 3,  Hazem E Okda 1 2 3,  Mohamed Elagawany 2 3,  Henry Politte 1 2,  Kevin Appourchaux 1 2,  Gonzalo Bedia-Diaz 2 3,  Isabelle Côté 4,  Lamees Hegazy 2 3,  Thomas P Burris 4 5,  Bahaa Elgendy 1 2 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri 63110, United States.
  • 2 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.
  • 3 Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, Missouri 63110, United States.
  • 4 Department of Cellular and Systems Pharmacology, University of Florida College of Pharmacy, Gainesville, Florida 32610, United States.
  • 5 University of Florida Genetics Institute, University of Florida School of Medicine, Gainesville, Florida 32610, United States.
PMID: 41432990 DOI: 10.1021/acs.jmedchem.5c02749
Abstract

REV-ERBα is a nuclear receptor transcriptional repressor involved in circadian rhythm, metabolism, inflammation, and myogenesis. Antagonizing REV-ERBα has emerged as a promising therapeutic strategy, yet few compounds with favorable pharmacokinetic profiles have been identified since SR8278. Here, we report the discovery and optimization of BE2012, a 3-aminoquinazolinone antagonist identified through high-throughput screening and refined via systematic structure-activity relationship studies. BE2012 exhibited potent REV-ERBα antagonism (EC50 = 0.285 μM), high nuclear receptor selectivity, minimal CNS off-target interactions, and improved ADME and pharmacokinetic properties, including a 22-fold longer half-life (t1/2 = 3.79 h) than SR8278. Molecular modeling revealed key hydrophobic and hydrogen-bonding interactions within the REV-ERBα ligand-binding pocket that stabilize BE2012 and explain its enhanced potency. In a murine model of acute muscle injury, BE2012 upregulated myogenic transcription factors and promoted muscle repair. Collectively, BE2012 represents a selective, pharmacokinetically favorable REV-ERBα/β antagonist with therapeutic potential in muscle regeneration and related diseases.

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