S107 hydrochloride is a small molecule compound that can specifically bind to RyR2, enhance calstabin2 binding, and inhibit Ca2+ leakage in RyR2 channels. S107 hydrochloride has oral activity and can penetrate the blood-brain barrier [1-2]. S107 hydrochloride can improve muscle function, prevent arrhythmia, and increase seizure threshold by stabilizing RyR FKBP complex, making it a promising candidate drug for the treatment of catechol polymorphic ventricular tachycardia (CPVT)[3-5].
In vitro, treatment of cardiomyocytes(carrying RyR2-I4587V mutation; CPVT-hiPSC-CMs) isolated from CPVT patients with 10μM S107 hydrochloride for 2-3h inhibited the frequency of DAD (Delayed Afterdepolarization) in cells in a concentration-dependent manner, producing an antiarrhythmic effect[3]. Treatment of Rbm20 KO rat cardiomyocytes with S107 hydrochloride (10μM) for 2-3h restored the damaged contractile properties of the cells to the level of WT cardiomyocytes, inhibited Ca2+ leakage, restored the intracellular Ca2+ level at rest, and alleviated the increase in ΔFFI caused by electrical stimulation[4].
In vivo, treatment of Ryr2-R2474S epilepsy model mice with an implantable osmotic pump and a dosage of 5mg/kg/h using S107 hydrochloride for 7 days can restore brain RyR channel activity to normal levels, repair mutated channel Ca2+ leakage, and prevent fatal arrhythmias[1]. S107 hydrochloride was administered to Huntington's disease model mice via drinking water at a dose of 75mg/kg/d for one month, preventing the dissociation of calstabin2 from cardiac RyR2, reducing endoplasmic reticulum Ca2+ leakage, and significantly improving motor coordination disorder and cognitive dysfunction[6]. Male arrhythmia mice with C57BL/10ScSc-Dmdmdx/J ingested S107 hydrochloride (25mg/100mL) daily in drinking water, which inhibited the depletion of calstabin1 in the RyR1 macromolecular complex in skeletal muscle, prevented the increase in the frequency of spontaneous SR Ca2+ release events, and alleviated the abnormal electrocardiogram and ventricular arrhythmia in mice[7].
References:
[1]. Lehnart S E, Mongillo M, Bellinger A, et al. Leaky Ca 2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice[J]. The Journal of clinical investigation, 2008, 118(6): 2230-2245.
[2]. Mei Y, Xu L, Kramer H H, et al. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1, 4-benzothiazepine derivative S107[J]. Biophysical Journal, 2013, 104(2): 443a.
[3]. Sasaki K, Makiyama T, Yoshida Y, et al. Patient-specific human induced pluripotent stem cell model assessed with electrical pacing validates S107 as a potential therapeutic agent for catecholaminergic polymorphic ventricular tachycardia[J]. PLoS One, 2016, 11(10): e0164795.
[4]. Guo W, Zhu C, Yin Z, et al. The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes[J]. Physiological Reports, 2021, 9(17): e15011.
[5]. Popa M A. Effect of Experimental Drug S107 on Accessory Protein Binding to the RyR[J]. 2012.
[6]. Dridi H, Liu X, Yuan Q, et al. Role of defective calcium regulation in cardiorespiratory dysfunction in Huntington’s disease[J]. JCI insight, 2020, 5(19): e140614.
[7]. Fauconnier J, Thireau J, Reiken S, et al. Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy[J]. Proceedings of the National Academy of Sciences, 2010, 107(4): 1559-1564.