hERG – Highlights from 30 Years as a Prime Secondary Pharmacology Target

Abstract The hERG potassium channel has been a critical focus in drug discovery and development for the past 30 years due to its role in cardiac repolarization and its association with drug‐induced torsade des pointes (TdP). An initial spike in TdP adverse events in the 1990s led to extensive regulatory and pharmaceutical industry efforts to mitigate this risk. The hERG channel, known for its promiscuous binding to various drugs, has unique structural features that contribute to its susceptibility to blockade. The absence of the Pro‐X‐Pro motif in its S6 transmembrane helix results in a wider inner vestibule, allowing diverse drugs to bind. Unique pore‐lining amino acids can facilitate that binding. The hERG margin, defined as the ratio between the hERG IC 50 and the therapeutic unbound plasma concentration, has been a key metric in assessing the risk of QTc prolongation and proarrhythmia. Despite the challenges, advancements in in silico and in vitro screening tools have improved the efficiency of hERG testing. The Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative has further refined the predictive models for proarrhythmia risk. The regulatory response, including the ICH S7B and E14 guidelines, has provided a framework for integrated risk assessment. The continued vigilance and optimization of compounds to avoid hERG blockade remain crucial in drug development, ensuring patient safety and minimizing the risk of drug‐induced cardiac events.