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

• Published in: Cell stem cell Vol. 27; no. 5; pp. 813 - 821.e6
• Main Authors: McKeithan, Wesley L., Feyen, Dries A.M., Bruyneel, Arne A.N., Okolotowicz, Karl J., Ryan, Daniel A., Sampson, Kevin J., Potet, Franck, Savchenko, Alex, Gómez-Galeno, Jorge, Vu, Michelle, Serrano, Ricardo, George, Alfred L., Kass, Robert S., Cashman, John R., Mercola, Mark
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2020
• Subjects: Action Potentials; Anti-Arrhythmia Agents - pharmacology; arrhythmia; cardiomyocyte; disease modeling; drug development; electrophysiology; high-throughput screening; Humans; Induced Pluripotent Stem Cells; long QT syndrome; medicinal chemistry; mexiletine; Myocytes, Cardiac; Patch-Clamp Techniques; long QT syndrome; electrophysiology; arrhythmia; high-throughput screening; cardiomyocyte; disease modeling; drug development; induced pluripotent stem cells; medicinal chemistry; mexiletine
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2020.08.003

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. [Display omitted] •LQT3 hiPSC cardiomyocytes recapitulate disease phenotypes and drug responses•Large-scale functional screens using LQT3 hiPSC-CMs enable drug optimization•Optimized mexiletine analogs decrease proarrhythmic liability and improve potency McKeithan et al. used large-scale functional screening of hiPSC cardiomyocytes carrying a mutation that causes an electrophysiological disorder (long QT syndrome type 3) to direct the chemical optimization of mexiletine, an antiarrhythmic drug used to treat the disease. Four new analogs have greater potency and less proarrhythmic liability relative to mexiletine.