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Role of hERG potassium channel assays in drug development

Birgit T Priest1, Ian M Bell, Maria L Garcia

  • 1Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey, USA. birgit_priest@merck.com

Channels (Austin, Tex.)
|October 14, 2008
PubMed

Insights

Screening drug candidates for hERG channel activity early is crucial. This prevents costly failures due to QT prolongation and potential cardiac arrhythmias, ensuring safer drug development.

Area of Science:

  • Pharmacology
  • Cardiology
  • Drug Safety

Background:

  • The hERG potassium channel is vital for cardiac repolarization.
  • Drug-induced blockade of hERG channels can lead to QT prolongation and fatal arrhythmias.
  • Early identification of hERG activity is essential to mitigate drug development risks.

Purpose of the Study:

  • To highlight the importance of early screening for hERG channel activity in drug discovery.
  • To discuss available methods for assessing hERG channel interactions.
  • To guide efficient structure-function relationship development for hERG inhibitors.

Main Methods:

  • Utilizing a range of assays, from high-throughput binding assays to detailed electrophysiological studies.
  • Employing functional assays such as membrane potential or rubidium flux measurements.
  • Integrating binding and functional assays with electrophysiology for comprehensive evaluation.

Main Results:

  • hERG channel blockade by diverse drug classes is a significant safety concern.
  • Early screening identifies compounds likely to cause QT prolongation.
  • A combination of screening methods allows for efficient structure-activity relationship determination.

Conclusions:

  • Early and thorough screening of drug candidates for hERG channel activity is paramount for preclinical safety.
  • A tiered approach using various assays can optimize the identification of safe drug leads.
  • Understanding hERG interactions early streamlines lead optimization and reduces late-stage attrition.

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