A place for high-throughput electrophysiology in cardiac safety:: Screening hERG cell lines and novel compounds with the IonWorks HT™ system

Several commercially available pharmaceutical compounds have been shown to block the I-Kr current of the cardiac action potential. This effect can cause a prolongation of the electrocardiogram QT interval and a delay in ventricular repolarization. The Food and Drug Administration recommends that all new potential drug candidates be assessed for I-Kr block to avoid a potentially lethal cardiac arrhythmia known as torsades de pointes. Direct compound interaction with the human ether-a-go-go-related gene (hERG) product, a delayed rectifier potassium channel, has been identified as a molecular mechanism of I-Kr block. One strategy to identify compounds with hERG liability is to monitor hERG current inhibition using electrophysiology techniques. The authors describe the IonWorks HT (TM) instrument as a tool for screening cell lines expressing hERG channels. Based on current amplitude and stability criteria, a cell line was selected and used to perform a 300-compound screen. The screen was able to identify compounds with hERG activity within projects that spanned different therapeutic areas. The cell line selection and optimization, as well as the screening abilities of the IonWorks HT (TM) system, provide a powerful means of assessing hERG active compounds early in the drug discovery pipeline.