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Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity.
Cell Stem Cell ( IF 23.9 ) Pub Date : 2020-09-14 , DOI: 10.1016/j.stem.2020.08.003
Wesley L McKeithan 1 , Dries A M Feyen 2 , Arne A N Bruyneel 2 , Karl J Okolotowicz 3 , Daniel A Ryan 3 , Kevin J Sampson 4 , Franck Potet 5 , Alex Savchenko 2 , Jorge Gómez-Galeno 3 , Michelle Vu 2 , Ricardo Serrano 2 , Alfred L George 5 , Robert S Kass 4 , John R Cashman 3 , Mark Mercola 1
Affiliation  

Modeling cardiac disorders with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes is a new paradigm for preclinical testing of candidate therapeutics. However, disease-relevant physiological assays can be complex, and the use of hiPSC-cardiomyocyte models of congenital disease phenotypes for guiding large-scale screening and medicinal chemistry have not been shown. We report chemical refinement of the antiarrhythmic drug mexiletine via high-throughput screening of hiPSC-CMs derived from patients with the cardiac rhythm disorder long QT syndrome 3 (LQT3) carrying SCN5A sodium channel variants. Using iterative cycles of medicinal chemistry synthesis and testing, we identified drug analogs with increased potency and selectivity for inhibiting late sodium current across a panel of 7 LQT3 sodium channel variants and suppressing arrhythmic activity across multiple genetic and pharmacological hiPSC-CM models of LQT3 with diverse backgrounds. These mexiletine analogs can be exploited as mechanistic probes and for clinical development.



中文翻译:

使用患者 hiPSC 心肌细胞重新设计抗心律失常药物以提高治疗潜力并降低毒性。

用人类诱导多能干细胞 (hiPSC) 衍生的心肌细胞对心脏疾病进行建模是候选疗法临床前测试的新范例。然而,与疾病相关的生理分析可能很复杂,并且尚未显示使用先天性疾病表型的 hiPSC 心肌细胞模型来指导大规模筛查和药物化学。我们通过高通量筛选来自携带 SCN5A 钠通道变体的心律失常长 QT 综合征 3 (LQT3) 患者的 hiPSC-CM,报告了抗心律失常药物美西律的化学改进。使用药物化学合成和测试的迭代循环,我们鉴定了具有更高效力和选择性的药物类似物,可抑制一组 7 个 LQT3 钠通道变体的晚期钠电流,并在具有不同背景的 LQT3 的多个遗传和药理学 hiPSC-CM 模型中抑制心律失常活动。这些美西律类似物可用作机械探针并用于临床开发。

更新日期:2020-11-06
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