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.
S107 hydrochloride是一种能够特异性结合RyR2、增强calstabin2结合并抑制RyR2通道Ca2+泄漏的小分子化合物，具有口服活性，能够穿透血脑屏障[1-2]。S107 hydrochloride能够通过稳定RyR-FKBP复合物改善肌肉功能，预防心律失常，提高癫痫发作阈值，是治疗儿茶酚能多态性心室心动过速（CPVT）的有前景候选药物[3-5]。
在体外，用10μM S107 hydrochloride处理从CPVT患者中分离诱导的心肌细胞（携带RyR2-I4587V突变；CPVT-hiPSC-CMs）2-3h，以浓度依赖性方式抑制细胞中DAD（延迟后除极）的频率，产生抗心律失常效应[3]。S107 hydrochloride（10μM）处理Rbm20 KO大鼠心肌细胞2-3h能够将细胞受损的收缩性特性恢复到WT心肌细胞水平，抑制了Ca2+泄漏，恢复了静息细胞内Ca2+水平，缓解了电刺激引起的∆FFI升高[4]。
在体内，通过植入式渗透泵使用S107 hydrochloride (5mg/kg/h)处理Ryr2-R2474S癫痫模型小鼠7天能够恢复脑RyR通道活动至正常水平，修复突变通道Ca2+泄漏情况，预防致命的心律失常的发生[1]。S107 hydrochloride以75mg/kg/d的剂量饮用水给药亨廷顿舞蹈病模型小鼠一个月，防止了calstabin2与心脏RyR2的解离，减轻了内质网Ca-2+泄漏情况，显著改善了运动协调失调及认知功能障碍[6]。 C57BL/10ScSc-Dmdmdx/J雄性心律失常小鼠每日饮水摄入S107 hydrochloride（25mg/100mL），能够抑制骨骼肌中RyR1大分子复合物中calstabin1的耗竭，防止了自发性SR Ca2+释放事件发生频率的增加，缓解了小鼠心电图异常和心室性心律失常的情况[7]。