HERG block, QT liability and sudden cardiac death

Area of Science:

• Pharmacology
• Cardiology
• Drug Safety

Background:

• Non-cardiac medications can prolong cardiac action potential duration (APD) and QT interval, potentially leading to Torsade de Pointes (TdP) and sudden cardiac death.
• TdP is a rare but serious arrhythmia, with QT prolongation serving as a clinical surrogate marker.
• APD/QT liability in non-cardiac drugs is typically linked to reduced hERG current, caused by direct channel blockade or impaired trafficking.

Purpose of the Study:

• To address the need for efficient methods to assess hERG channel liability during drug development.
• To introduce a novel high-throughput screening assay for detecting hERG channel blockers and trafficking inhibitors.
• To improve the prediction and mitigation of drug-induced cardiac risks.

Main Methods:

• Development and validation of a novel high-throughput screening (HTS) assay.
• The HTS assay is designed to detect direct hERG channel blockade.
• The HTS assay also identifies compounds that inhibit hERG channel trafficking.

Main Results:

• The new HTS assay provides a scalable method for evaluating hERG liability.
• The assay can identify drugs that directly block the hERG channel.
• The assay can also detect drugs that interfere with hERG channel trafficking, a key mechanism for APD prolongation.

Conclusions:

• A novel high-throughput screening assay has been developed to identify non-cardiac drugs with hERG liability.
• This assay facilitates early detection of potential cardiac risks during lead optimization.
• The HTS method offers improved throughput compared to traditional patch clamp techniques for assessing hERG channel interactions.