Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation

Human ether-a-go-go-related gene (hERG; K_v 11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The interference from accompanying block of Ca_v 1.2 and Na_v 1.5 channels was investigated along with an in silico AP model.

Drug-induced changes in APD were assessed in hiPSC-CMs using voltage-sensitive dyes. The IC₅₀ values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D₁₅₀ ) required to prolong the APD at 90% (APD₉₀ ) repolarization by 50%.

The D₁₅₀ in hiPSC-CMs was linearly correlated with IC₅₀ of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Ca_v 1.2 and/or Na_v 1.5 in a channel state-dependent manner. Adding Ca_v 1.2 and Na_v 1.2 block to the in silico model recapitulated the direction but not the extent of the APD change.

Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC-CMs. The compounds that do not correlate have additional effects including concomitant block of Ca_v 1.2 and/or Na_v 1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects.