hERG subunit composition determines differential drug sensitivity.

Area of Science:

• Pharmacology
• Cardiovascular Science
• Drug Safety

Background:

• Drug-induced long QT syndrome is a risk mitigated by hERG channel screening.
• Current screening often uses only the hERG 1a subunit, neglecting the hERG 1b subunit's role in I(Kr) current.

Purpose of the Study:

• To compare the sensitivity of hERG 1a and hERG 1a/1b channels to a diverse set of compounds.
• To determine if differing sensitivities affect safety margins and risk stratification for drug-induced long QT syndrome.

Main Methods:

• Utilized the IonWorks™ electrophysiology device for high-throughput screening.
• Compared compound potency (IC₅₀ values) against hERG 1a and hERG 1a/1b channels expressed in HEK293 cells.
• Employed alternating columns of cell types to minimize variability in compound testing.

Main Results:

• Most compounds showed similar potency against hERG 1a and 1a/1b channels.
• Fluoxetine (Prozac) was more potent against hERG 1a/1b channels, reducing its safety margin.
• E-4031 and dofetilide were more potent blockers of hERG 1a channels compared to 1a/1b channels.

Conclusions:

• Current hERG screening assays may underestimate or overestimate drug risks for torsades de pointes arrhythmia.
• Utilizing both hERG 1a and 1a/1b subunits in screening could lead to more accurate safety assessments.
• Stratified risk analysis based on subunit-specific sensitivities may be necessary for certain drug candidates.