Discovery & Development Lead Discovery Ion Channels
IonWorks hERG channel assay Correlation between IonWorks IC50 values and published values obtained using manual patch clamp for seven reference compounds, using PrecisION recombinant hERG cell line (Millipore). Most fall on the line of equivalence (black), or within a 3-fold range of this (blue dotted lines), indicating good correlation between methodologies.
Ion Channels In Drug Discovery and Safety Pharmacology Ion channels regulate electrical activity in excitable cells, and many roles in non-excitable tissues continue to be uncovered. Ion channels are important therapeutic targets for conditions including arrhythmia, hypertension, local anesthesia, pain, stroke, epilepsy, depression, bipolar disorder, COPD, autoimmune disorders and diabetes. Not only are ion channels important drug targets, but they also regulate safety pharmacology of virtually all drugs. Many drugs have been shown to block the human ether-a-go-go (hERG) ion channel, delaying repolarization of the cardiac action potential. This can initiate the arrhythmia known as Torsades de Pointes (TdP) with fatal consequences.
Recently, automated electrophysiology systems have revolutionized ion channel drug discovery and safety pharmacology testing by facilitating ion channel-focused library screening, medicinal chemistry and safety pharmacology.
hERG screening for small molecule inhibitors of hERG. hERG Membrane Preparation (10 μg/well) was characterized by hERG screening with known hERG blockers in a competition binding assay. The membranes were incubated with 3.0 nM [3H]-Astemizole and increasing concentrations of unlabeled compounds to determine sample activity and rank order.
PrecisionION Recombinant hERG Potassium Ion Channel Membrane Preparation To complement our functional assays, Millipore provides membranes for hERG radioligand binding assays. These have been validated using several different radioligands and provide comparable data to that found in the literature.
Better hERG Screening
The PrecisION Recombinant hERG Potassium Ion Channel Membrane Preparation enables high-throughput binding assays for rapid, cost-effective hERG screening. Cardiotoxicity caused by hERG potassium channel blockade and can result in the costly withdrawal of drugs or late-stage termination of drug development. Detecting potential cardiotoxicity early can save significant cost and time.
Advantages of PrecisION hERG Membrane Preparations:
High functional expression and specific binding
Created from stable cell lines for consistent performance
Validated using three different radioligands (Astemizole, Dofetilide, BeKm-1)
Available in bulk quantities
How does hERG channel blockage cause cardiotoxicity?
The human ether-à-go-go-related gene (hERG) encodes the potassium ion channel responsible for the delayed rectified potassium current IKr. Several classes of drugs can inhibit IKr, resulting in delayed repolarization (measured as a long QT interval) and possible cardiotoxicity. As a result, the U.S. FDA and ICH S7B guidelines have set out a non-clinical testing strategy to assess the effects of pharmaceuticals on ventricular repolarisation and proarrhythmic risk.