生物活性

• 描述S107 is a RyR-selective 1,4-benzothiazepine derivative that stabilizes RyR2 channels by enhancing the binding affinity of calstabin2 to mutant and/or PKA-phosphorylated channels. S107 increased FKBP12 binding to RyR1 in SR vesicles in the presence of reduced glutathione and the NO-donor NOC12, with no effect in the presence of oxidized glutathione. S107 can reverse the harmful effects of redox active species on SR Ca(2+) release in skeletal muscle by binding to RyR1 low affinity sites^[3]. Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT(catecholaminergic polymorphic ventricular tachycardia)-hiPSC-CMs(cardiomyocytes) presenting DADs to 25%^[4]. S107 restored elevated intracellular Ca2+ to normal levels and ameliorated cardiomyocyte contractile properties in isolated cardiomyocytes from 6-month-old Rbm20 KO rats^[5]. S107 is able to restore motor function in aging Drosophila to young levels, and this effect of S107 is absent in calstabin (FK506-BP2) mutants^[6].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00447421	-	-	Terminated(Interim results of ... more >>another trial showed inferior activity of treatment) Collapse <<	-	-
  NCT00447421	Small Cell Lung Cancer ... more >> Carcinoma, Small Cell SCLC Collapse <<	Phase 1 Phase 2	Terminated(Interim results of ... more >>another trial showed inferior activity of treatment) Collapse <<	-	Belgium ... more >> For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Leuven, Belgium, 3000 Netherlands For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Amsterdam, Netherlands, 1081 HV For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Den Bosch, Netherlands, 5211 NL For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Rotterdam, Netherlands, 3075 EA Collapse <<
  NCT00548483	Airway Obstruction	Phase 2	Unknown	May 2008	Taiwan ... more >> No. 92, SEC. 2, CHUNG SHAN N. RD, TAIPEI, TAIWAN. Recruiting Taipei, Taiwan, 104 Contact: Chao-Hsien Lee, MD    886-2-23926589    L49428@ms2.mmh.org.tw Collapse <<

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• 参考文献

• [1] Matecki S, Dridi H, et al. Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation. Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9069-74.

  [2] Bellinger AM, Reiken S, et al. Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle. Nat Med. 2009 Mar;15(3):325-30.

  [3] Mei Y, Xu L, Kramer HF, Tomberlin GH, Townsend C, Meissner G. Stabilization of the skeletal muscle ryanodine receptor ion channel-FKBP12 complex by the 1,4-benzothiazepine derivative S107. PLoS One. 2013;8(1):e54208

  [4] Sasaki K, Makiyama T, Yoshida Y, Wuriyanghai Y, Kamakura T, Nishiuchi S, Hayano M, Harita T, Yamamoto Y, Kohjitani H, Hirose S, Chen J, Kawamura M, Ohno S, Itoh H, Takeuchi A, Matsuoka S, Miura M, Sumitomo N, Horie M, Yamanaka S, Kimura T. Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia. PLoS One. 2016 Oct 20;11(10):e0164795

  [5] Guo W, Zhu C, Yin Z, Zhang Y, Wang C, Walk AS, Lin YH, McKinsey TA, Woulfe KC, Ren J, Chew HG Jr. The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes. Physiol Rep. 2021 Sep;9(17):e15011

  [6] Kreko-Pierce T, Azpurua J, Mahoney RE, Eaton BA. Extension of Health Span and Life Span in Drosophila by S107 Requires the calstabin Homologue FK506-BP2. J Biol Chem. 2016 Dec 9;291(50):26045-26055

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