S107 is an orally available, blood-brain barrier-permeable compound that stabilizes RyR2 channels by enhancing the binding of calstabin 2 to the mutant Ryr2-R2474S channel[1]. S107 augments the FKBP12-mediated decrease in channel activity and reverses the harmful effects of redox-active species on sarcoplasmic reticulum (SR) Ca2+ release in skeletal muscle by binding to RyR1 low-affinity sites[2]. S107 has been widely used in preclinical models to prevent ventricular arrhythmias, epileptic seizures, and atrial fibrillation[3].
In vitro, S107 treatment (10µM) for 2h at room temperature restored the intracellular Ca2+ levels and improved contractile properties in cardiomyocytes from Rbm20 knockout rats[4]. Treatment with 10µM S107 for 48 hours rescued the cell dysfunction induced by Aβ42 in mouse hippocampal neurons[5]. Incubation of SH-SY5Y cells with 1µM S107 for 12 hours reduced β-amyloid precursor protein (βAPP) processing, Aβ42 production, and Ca2+ signaling[6].
In vivo, continuous administration of S107 via subcutaneous osmotic pump at a dose of 5mg/kg/h for 7 consecutive days suppressed seizures and improved survival in Ryr2RS/WT mice[1]. Oral administration of S107 (75mg/kg/day) for 21 days effectively alleviated the cognitive decline induced by hindlimb suspension (HU) in C57BL/6NJ 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 F, et al. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1, 4-benzothiazepine derivative S107[J]. PloS one, 2013, 8(1): e54208.
[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] Hidisoglu E, Chiantia G, Franchino C, et al. The ryanodine receptor–calstabin interaction stabilizer S107 protects hippocampal neurons from GABAergic synaptic alterations induced by Abeta42 oligomers[J]. The Journal of Physiology, 2022, 600(24): 5295-5309.
[6] Bussiere R, Lacampagne A, Reiken S, et al. Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor[J]. Journal of Biological Chemistry, 2017, 292(24): 10153-10168.
[7] Hao J, Zhang Y, Li N, et al. Microgravity‐Induced Cognitive Decline: Investigating the Pathogenic Mechanisms of RyR2 Hyperphosphorylation and S107 Intervention[J]. The FASEB Journal, 2025, 39(13): e70743.