What is SLU-PP-332?
SLU-PP-332 is a synthetic small molecule agonist selectively targeting estrogen-related receptor alpha (ERRα), a nuclear receptor known to regulate genes involved in mitochondrial biogenesis and oxidative metabolism. Developed through structure-based design from the ERRβ/γ-preferring scaffold GSK4716, SLU-PP-332 exhibits enhanced ERRα activity by exploiting key π-π interactions within the receptor's ligand-binding domain (Billon et al. 2022). The compound demonstrates nanomolar potency (EC₅₀ ~8–98 nM for ERRα) and significantly less activation of ERRβ and ERRγ, establishing its receptor selectivity (Billon et al. 2022; Mahale & Girase 2024).
Functional studies reveal that SLU-PP-332 increases the expression of ERRα target genes such as Pdk4, Ddit4, and Slc25a25, enhancing mitochondrial respiration and biogenesis in C2C12 myocytes (Billon et al. 2022; Nasri 2024). In vivo administration in mice results in elevated oxidative muscle fiber content, increased mitochondrial DNA, and improved markers of oxidative phosphorylation, without observed toxicity. Transcriptomic analysis showed significant overlap between the gene expression signatures induced by SLU-PP-332 and those activated by acute aerobic exercise—most notably in genes regulating energy metabolism and circadian rhythm (Billon et al. 2022). These effects were abrogated in skeletal muscle-specific ERRα knockout models, confirming the compound’s mechanism of action via ERRα (Billon et al. 2022).
References
Billon, C., Sitaula, S., Banerjee, S., Welch, R., Elgendy, B., Hegazy, L., ... & Burris, T. P. (2022). A Synthetic ERRα Agonist Induces an Acute Aerobic Exercise Response and Enhances Exercise Capacity. bioRxiv. https://doi.org/10.1101/2022.10.05.510974
Mahale, B. M., & Girase, A. M. (2024). Unlocking the potential: SLU-PP-332 and the future of exercise enhancement and metabolic health. Research Journal of Science and Technology, 16(4). https://doi.org/10.52711/2349-2988.2024.00047
Nasri, H. (2024). New hopes on “SLU-PP-332” as an effective agent for weight loss with indirect kidney protection efficacy; a nephrology point of view. Journal of Renal Endocrinology, 10, e25143. https://doi.org/10.34172/jre.2024.25143