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