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Updated: Nov 7, 2025
Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes hPSC-CMs Using Multi-electrode Arrays MEAs
Published on: May 12, 2017
Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes
John R Cashman1, Daniel Ryan1, Wesley L McKeithan2,3
1Human BioMolecular Research Institute, San Diego, California 92121, United States.
Abstract:
Ventricular cardiac arrhythmia (VA) arises in acquired or congenital heart disease. Long QT syndrome type-3 (LQT3) is a congenital form of VA caused by cardiac sodium channel (INaL) SCN5A mutations that prolongs cardiac action potential (AP) and enhances INaL current. Mexiletine inhibits INaL and shortens the QT interval in LQT3 patients. Above therapeutic doses, mexiletine prolongs the cardiac AP. We explored structure-activity relationships (SAR) for AP shortening and prolongation using dynamic medicinal chemistry and AP kinetics in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using patient-derived LQT3 and healthy hiPSC-CMs, we resolved distinct SAR for AP shortening and prolongation effects in mexiletine analogues and synthesized new analogues with enhanced potency and selectivity for INaL. This resulted in compounds with decreased AP prolongation effects, increased metabolic stability, increased INaL selectivity, and decreased avidity for the potassium channel. This study highlights using hiPSC-CMs to guide medicinal chemistry and "drug development in a dish".
Insights
Researchers developed new drug analogues to treat Long QT syndrome type-3 (LQT3) by targeting cardiac sodium channels. This approach aims to shorten the cardiac action potential without causing dangerous prolongation, improving patient outcomes.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Medicinal Chemistry
Background:
- Ventricular arrhythmia (VA) is linked to acquired or congenital heart disease.
- Long QT syndrome type-3 (LQT3), a congenital VA, stems from SCN5A mutations affecting the cardiac sodium channel (INaL), prolonging cardiac action potential (AP).
- Mexiletine, while effective at therapeutic doses for LQT3, can prolong AP at higher concentrations.
Purpose of the Study:
- To investigate structure-activity relationships (SAR) for AP shortening and prolongation effects of mexiletine analogues.
- To synthesize novel analogues with enhanced potency and selectivity for INaL.
- To develop safer LQT3 therapeutics using a
- drug development in a dish
- approach.
Main Methods:
- Utilized dynamic medicinal chemistry and AP kinetics.
- Employed human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), including patient-derived LQT3 models and healthy controls.
- Synthesized and characterized novel mexiletine analogues.
Main Results:
- Resolved distinct SAR for AP shortening and prolongation of mexiletine analogues.
- Developed new analogues with improved potency and selectivity for INaL.
- Achieved compounds with reduced AP prolongation, enhanced metabolic stability, and decreased off-target potassium channel avidity.
Conclusions:
- hiPSC-CMs are valuable tools for guiding medicinal chemistry in drug development.
- Novel mexiletine analogues demonstrate potential for safer and more effective LQT3 treatment.
- This study advances the concept of
- drug development in a dish
- for cardiac channelopathies.
