• Patchliner

    兼顾科研与工业的全自动膜片钳系统
  • Patchliner

    自主生产与质量控制的耗材
  • Patchliner

    拥有超过10年实验设计与支持的经验
  • Dynamite8

    Automated Dynamic Clamp
  • Patchliner

    拥有所有手动膜片钳的特征与优点

2020 - Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity

icon pl Patchliner and  icon sp96 SyncroPatch 768PE (a predecessor model of the SyncroPatch 768i instrument) publication in Cell Stem Cell (2020)

Authors:
McKeithan W. L., Feyen D.A.M., Bruyneel A.A.N., Okolotowicz K.J., Ryan D.A., Sampson K.J., Potet F., Savchenko A., Gómez-Galeno J., Vu M., Serrano R., George Jr. A.L., Kass R.S., Cashman J.R., Mercola M.

Journal:
Cell Stem Cell (2020) doi: 10.1016/j.stem.2020.08.003


Abstract:

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.


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