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HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk
Barbara A Wible1, Peter Hawryluk, Eckhard Ficker
1ChanTest Inc, ChanXpress Inc, Cleveland, OH, 44128, USA. bwible@chantest.com
Insights
A new assay, HERG-Lite, accurately predicts drug-induced hERG risk by identifying both channel blockers and trafficking inhibitors. This cost-effective assay aids early drug safety testing for cardiotoxicity.
Area of Science:
- Cardiovascular Pharmacology
- Drug Discovery and Development
- Molecular Toxicology
Background:
- Non-antiarrhythmic drugs (NARDs) can cause QT prolongation and Torsades de Pointes (TdP) by blocking the hERG potassium channel.
- Alternatively, some drugs induce Long QT Syndrome (LQTS) and TdP by inhibiting hERG trafficking, not direct channel block.
- Accurate prediction of these hERG-related risks is crucial for cardiotoxicity assessment in drug development.
Purpose of the Study:
- To develop and validate a novel, comprehensive assay for early prediction of drug-induced hERG risks.
- To create an inexpensive, rapid assay capable of identifying both hERG channel blockers and trafficking inhibitors.
Main Methods:
- Developed HERG-Lite, an antibody-based chemiluminescent assay using two mammalian cell lines.
- One cell line detects inhibition of hERG trafficking; the other identifies hERG blockers via pharmacological chaperoning.
- Validated HERG-Lite using a panel of 100 drugs (50 blockers, 50 non-blockers).
Main Results:
- HERG-Lite demonstrated 100% accuracy, correctly predicting hERG risk for all tested compounds.
- No false positives or negatives were observed in the validation study.
- Detected hERG blockers were classified as either direct blockers (Class B) or complex (Class C, involving trafficking inhibition).
Conclusions:
- HERG-Lite is a highly effective assay for predicting drug-induced hERG risk.
- The assay accurately identifies both hERG channel blockers and trafficking inhibitors.
- HERG-Lite offers a rapid, cost-effective, and comprehensive solution for non-clinical drug safety testing.
Introduction:
Direct block of I(Kr) by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current I(Kr), however. We have shown recently that two drugs in clinical use do not block hERG but produce long QT syndrome (LQTS) and TdP by inhibiting trafficking of hERG to the cell surface. To address the need for an inexpensive, rapid, and comprehensive assay to predict both types of hERG risk early in the drug development process, we have developed a novel antibody-based chemiluminescent assay called HERG-Lite.
Methods:
HERG-Lite monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers.
Results:
HERG-Lite correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition).
Discussion:
HERG-Lite is the most comprehensive assay available for predicting drug-induced hERG risk. It accurately predicts both channel blockers and trafficking inhibitors in a rapid, cost-effective manner and is a valuable non-clinical assay for drug safety testing.
