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

Wesley L. McKeithan, Dries A.M. Feyen, Arne A.N. Bruyneel, Karl J. Okolotowicz, Daniel A. Ryan, Kevin J. Sampson, Franck Potet, Alex Savchenko, Jorge Gómez-Galeno, Michelle Vu, Ricardo Serrano, Alfred L. George, Robert S. Kass, John R. Cashman, Mark Mercola*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCell stem cell
DOIs
StateAccepted/In press - 2020

Keywords

  • arrhythmia
  • cardiomyocyte
  • disease modeling
  • drug development
  • electrophysiology
  • high-throughput screening
  • induced pluripotent stem cells
  • long QT syndrome
  • medicinal chemistry
  • mexiletine

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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  • Cite this

    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, A. L., Kass, R. S., Cashman, J. R., & Mercola, M. (Accepted/In press). Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity. Cell stem cell. https://doi.org/10.1016/j.stem.2020.08.003