Safety assessment studies on ion channels

ChanPharm’s safety assessment panel covers key ion channels and enables identification of adverse drug reactions. Profiling against a broad panel of these off-targets at an early stage of drug development supports lead generation, lead optimization and selection of a drug candidate..

ChanPharm’s proarrhythmia assay

At an early stage of drug development the proarrhythmic potential is most commonly determined by evaluating effects on the HERG ion channel.

However, not all HERG blockers cause QT-prolongation and life threatening torsades de pointes. This is caused by the fact that many compounds block several ion channels simultaneously (multichannel block) resulting in complex time- and voltage-dependent interplay of drug effects that could prevent repolarization abnormalities such as early after depolarisations (EADs).

In other words, an overestimation of HERG inhibition can prevented the development of potentially valuable therapeutics.

ChanPharm accounts for multi ion channel effects and offers (beside our well established HERG screen) studies on a panel of cardiac ion channels. Similar proposals were recently made by the comprehensive in vitro proarrhythmia assay initiative (CiPA, link to CIPA document online).

Studying proarrhythmic effects on stem cell-derived cardiomyocytes

Studying drug effects on action potentials in induced pluripotent stem cell-derived human cardiomyocytes (hiPSC-CMs) can be of key importance for selection of a drug candidate.

This human test system enables the detection of action potential prolongation (related to QT risk) and early after depolarisations (EADs triggering torsades de pointes). ChanPharm’s scientists substantially contributed to development and validation of cardiac action potential duration (APD) assays making use of fluorescent voltage-sensitive probes.

In silico reconstruction of action potentials in stem cell-derived cardiomyocytes

For drugs it is impossible to translate the inhibition of a cardiac ion channel to a delayed repolarization or a propensity for proarrhythmia. In silico reconstructions of ventricular electrical activity can, therefore, be of great help to understand proarrhythmic drug effects.

We therefore perform in silico reconstruction of drug effects on action potentials for our clients. Scientists of ChanPharm made and make important contributions to this emerging new technology (e.g. Saxena et al. 2017).

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