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

  • Cell Stem Cell. 2020 Nov 5;27(5):813-821.e6. 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 Jr  5 ,  Robert S Kass  4 ,  John R Cashman  3 ,  Mark Mercola  6
Affiliations
  • 1. Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA.
  • 2. Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 3. Human BioMolecular Research Institute, San Diego, CA 92121, USA.
  • 4. Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
  • 5. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 6. Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA. Electronic address: [email protected].
PMID: 32931730 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.

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