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

Area of Science:

• Cardiovascular Research
• Stem Cell Biology
• Pharmacology

Background:

• Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes offer a novel platform for preclinical drug testing.
• Utilizing hiPSC-cardiomyocyte models for congenital disease phenotypes in drug screening and medicinal chemistry remains underexplored.

Purpose of the Study:

• To chemically refine the antiarrhythmic drug mexiletine.
• To develop potent and selective drug analogs for long QT syndrome 3 (LQT3) using hiPSC-cardiomyocyte models.

Main Methods:

• High-throughput screening of hiPSC-cardiomyocytes from LQT3 patients with SCN5A variants.
• Iterative medicinal chemistry synthesis and testing of drug analogs.
• Assessing inhibition of late sodium current and suppression of arrhythmic activity.

Main Results:

• Identified mexiletine analogs with enhanced potency and selectivity for inhibiting late sodium current.
• Demonstrated efficacy across a panel of 7 LQT3 sodium channel variants.
• Showcased suppression of arrhythmic activity in diverse hiPSC-cardiomyocyte models of LQT3.

Conclusions:

• Developed novel mexiletine analogs as potential therapeutics for LQT3.
• These analogs can serve as mechanistic probes for further research.
• The findings support the clinical development of these refined antiarrhythmic agents.