Correlation between hERG channel inhibition and action potential prolongation

Background and purpose hERG (Kv11.1) 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 hiPSC-CMs. The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in-silico action potential (AP) model. Experimental approach Drug-induced changes in APD were assessed in hiPSC-CMs using voltage sensitive dyes. The half-maximal inhibitory concentrations (IC50) of hERG current by dofetilide and 13 derivatives were estimated in a HEK293 expression system. The relative potency of the drug on APD was estimated by calculating the drug dose (D150) required to prolong the APD at 90% (APD90) repolarisation by 50%. Key results The D150 in hiPSC-CMs was linearly correlated with IC50 of hERG current (r=0.94, p<0.001). In-silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, these compounds also inhibited Cav1.2 and/or Nav1.5 in a channel state-dependent manner. Adding Cav1.2 and Nav1.2 block to the in-silico model recapitulated the direction but not the extent of the APD change. Conclusions and implications 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 Cav1.2 and/or Nav1.5 channels. In-silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects.