A Place for High-Throughput Electrophysiology in Cardiac Safety: Screening hERG Cell Lines and Novel Compounds with the Ion Works HTTM SystemNon-Clinical Drug Discovery
Molecular Devices Corporation, Sunnyvale, CA
Discovery Technologies, Hoffmann–La Roche, Inc., Nutley, NJ Several commercially available pharmaceutical compounds have been shown to block the I Krcurrent of the cardiac action potential. This effect can cause a prolongation of the electrocardiogram QTinterval and a delay in ventricular repolarization. The Food and Drug Administration recommends that all new potential drug candidates be assessed for I Krblock 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 withh ERGliability is to monitor hERGcurrent inhibition using electrophysiology techniques. The authors describe the Ion Works HT TMinstrument 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 Ion Works HT TMsystem, provide a powerful means of assessinghERGactive compounds early in the drug discovery pipeline.
Key Words: Ion Works • electrophysiology • hERG • high throughput
This version was published on December
1, 2005 Journal of Biomolecular Screening, Vol. 10, No. 8,
832-840 (2005) This article has been cited by other articles:
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