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In vitro profiling against ion channels beyond hERG as an early indicator of cardiac risk
Mao Xiang Chen1, Ray M Helliwell, Jeff J Clare
1GlaxoSmithKline plc, Biological Reagents & Assay Development, Hertfordshire, UK.
Abstract:
Acquired long QT syndrome is a major cause of drug withdrawals and the failure of compounds during development. Traditionally, in vitro cardiac liability screens have been low throughput and expensive, and have used primary animal cells or tissues that are not necessarily predictive of the human heart. Recent advances in ion channel assay technologies, particularly automated patch clamp, have enabled the early liability screening of individual ion channels at medium-to-high throughput and with acceptable fidelity. The primary aim of this first-tier screening is to aid prioritization of early-stage compounds for progression along the screening cascade. Potential liabilities can be flagged to enable follow-up studies to be initiated if and when compounds approach the costlier stages of development. To date, cardiac safety screening has been focused on hERG channel. This article examines the rationale for the early screening of cardiac channels beyond hERG as part of an integrated strategy for in vitro evaluation of cardiac risk, and reviews recent developments in the relevant technologies.
Insights
Acquired long QT syndrome, a risk in drug development, can be identified earlier. New high-throughput screening methods for cardiac ion channels beyond hERG improve early drug safety assessments.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Drug Development
Background:
- Acquired long QT syndrome is a significant cause of drug attrition.
- Traditional cardiac liability screens are low-throughput, costly, and use animal models not predictive of human response.
- Early detection of cardiac risks is crucial for successful drug development.
Purpose of the Study:
- To evaluate the rationale for screening cardiac ion channels beyond hERG.
- To review advancements in in vitro technologies for cardiac safety assessment.
- To propose an integrated strategy for early in vitro cardiac risk evaluation.
Main Methods:
- Utilizing automated patch clamp technology for medium-to-high throughput screening.
- Focusing on individual ion channel assays for early liability detection.
- Implementing a tiered screening approach for compound prioritization.
Main Results:
- Automated patch clamp enables efficient screening of individual ion channels.
- Early screening beyond hERG can identify potential cardiac liabilities.
- This approach aids in prioritizing compounds for further development.
Conclusions:
- Screening cardiac ion channels beyond hERG is essential for comprehensive in vitro cardiac risk assessment.
- Advancements in assay technologies facilitate early and efficient cardiac safety evaluations.
- An integrated strategy improves the prediction of drug-induced cardiac events.
