ML-SA5 is a potent TRPML1 cation channel agonist that activates the entire endosomal TRPML1 (ML1) current in DMD myocytes with an EC50 of 285 nM and is more potent than ML-SA1. ML-SA5 has anticancer activity and can inhibit tumour growth[1].
ML-SA5(1-100 μM, 24 h) has some cell-targeting specificity and induces substantial cell death in M12 and MeWo cells, but fully preserves normal melanocytes. It also causes a loss of mitochondrial membrane potential in M12 cells[1].
ML-SA5 (i.p., 2-5 mg/kg, daily, 2 weeks) reduces muscle necrosis in MDX mice by more than 70% and reduces central nucleated fibers, suggesting that ML-SA5 can improve muscle atrop in mdx mice in vivo by promoting myosin repair, but has no effect in ML1 knockout mice. Moreover, ML-SA5 reduces skeletal and cardiac muscle damage in mdx mice through ML1 upregulation[2].
[1]. Wanlu Du, et al. Lysosomal Zn2+release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma. Cell Rep. 2021 Oct 19;37(3):109848.
[2]. Lu Yu, et al. Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrop in mouse models. Sci Adv. 2020 Feb 7;6(6):eaaz2736.