Drug-induced hERG block and long QT syndrome

Abstract

Drug-induced long QT syndrome is a cardiac safety issue that all drugs seeking approval must currently address, in part via in vitro electrophysiological testing of the drug's effects on the function of the human Ether-à-go-go Related Gene (hERG) potassium channel. This regulatory strategy has also been scientifically successful, in that these in vitro assays are cheaper and faster than are many other surrogates for arrhythmogenic risk, including QT prolongation in humans and action potential prolongation in cardiomyocytes. In some ways hERG assays are also more sensitive to the underlying repolarization anomalies that lead to the risk of the Torsades de pointes arrhythmia. In addition, the higher throughput of hERG assays combined with advances in our understanding of the molecular structures underlying this pathophysiology have led to new approaches in the medicinal chemistry of "designing out" hERG liability from lead compounds. While generally effectual, hERG screening produces some false positives: drugs with an apparent liability that are known not to be clinically arrhythmogenic. New technologies continue to be developed to improve hERG screening, while further insights into the molecular pharmacology of hERG and cardiac repolarization are providing avenues to mitigate and make sense of the lack of torsadogenic specificity in extant hERG assays.