BE2012 a Novel, REV-ERB Antagonist that Promotes Regenerative Myogenesis In Vivo with Substantially Improved Pharmacokinetics Relative to SR8278

ABSTRACT: Pharmacological inhibition of REV-ERBs has emerged as a potential therapeutic strategy for several diseases with unmet medical needs. Indeed, chronic treatment with SR8278, a synthetic REV-ERB antagonist, has mitigated pathology in various preclinical models of human musculoskeletal and neurological diseases, including Duchenne muscular dystrophy, epilepsy, Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. However, SR8278, the first and most widely used REV-ERB antagonist, has poor pharmacokinetic properties, which limits its utility. The REV-ERBs (α and β) are widely expressed nuclear receptors that function as ligand-dependent transcriptional repressors and the therapeutic potential for inhibition of these receptors remains unclear due to the lack of adequate pharmacological tools. Here, we report BE2012, a significantly improved REV-ERB antagonist with >22-fold longer half-life than SR8278. In a cell-based reporter assay, BE2012 exhibited greater potency toward REV-ERBα (EC50=0.38 μM) and REV-ERBβ (EC50=0.57 μM) compared to SR8278. Notably, in primary myoblast differentiation assays, BE2012 outperformed SR8278 in increasing the proportion of MyoG+ cells as well differentiation and fusion indices. In a cardiotoxin-induced muscle injury model, both BE2012 and SR8278 led to increased myofiber cross-sectional area (22-34% higher than controls). Lastly, transcriptomic profiling revealed remarkable overlap of differentially expressed genes between the two compounds, with oxidative phosphorylation (OXPHOS) and mitochondrial protein complex emerging as the most significantly enriched pathways for both ligands, which have been shown to accelerate regenerative myogenesis. These results establish BE2012 as a refined REV-ERB antagonist for in vivo applications and a valuable tool for deeper exploration of the therapeutic potential of inhibiting REV-ERB activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE325292 | GEO | 2026/08/20

REPOSITORIES: GEO