hERG Screening for Drug Discovery

hERG screening evaluates whether a compound inhibits the hERG (Kv11.1) potassium channel, an important contributor to cardiac repolarisation. Inhibition of hERG can delay repolarisation and is associated with QT interval prolongation and an increased risk of Torsades de Pointes (TdP).

ApconiX provides rapid, high-quality functional hERG screening using automated and manual patch clamp electrophysiology. Our scientists help drug discovery teams identify potential liabilities early, guide medicinal chemistry and make better-informed candidate selection decisions.

The Reductionist Approach | Apconix

Read Dr Michael Morton’s blog on the background to hERG testing: The Reductionist Approach

Conceptual Illustration Of A Red Ion Channel Within A Grey Cell Membrane, With A Heart Model In The Background.
Scientist In A White Lab Coat Reviewing Plotted Traces On A Computer Monitor In A Bright Laboratory.

Why early hERG screening matters

Drugs can have off-target effects. Terfenadine, an antihistamine withdrawn from the market because of its cardiac risks, is a well-known example of the consequences of hERG inhibition.

The ICH S7B guideline, introduced in 2005, describes a nonclinical testing strategy for assessing a compound’s potential to delay ventricular repolarisation.

Testing early for hERG inhibition supports the de-risking of drug pipelines and can help reduce wasted time and costs. Patch clamp electrophysiology provides direct, functional data to characterise a compound’s effects on hERG and support the assessment of safety margins.

A compound that blocks hERG may still have development potential. An integrated approach helps place these findings in a wider cardiac safety context. ApconiX also provides testing of the CiPA ion channel panel, in silico modelling and cardiac MEA.

What you will benefit from

  • Access to ApconiX scientists who will tailor our service specifically to your needs and better advise you on your next steps
  • High quality ion channel profiling matched to your design-make-test cycle
  • An average turnaround time for hERG data of less than 4 days following receipt of customer compounds
  • Access to expertise from a broad pool nonclinical safety experts
Ion Channel Screening And Assay Development | Apconix
Herg Screening Data

Our services include:

  • Ion channel screening for hERG
  • Bespoke assay and cell line development
  • Expertly performed direct functional electrophysiology measurements with fewer artefacts than ligand binding or fluorescence assays
  • Testing on the latest generation automated electrophysiology platforms (QPatch II and Patchliner) with the capacity for large numbers of compounds
  • We additionally provide manual patch clamp services

Cardiac ion channel screening beyond hERG

By working with ApconiX you will benefit from our combined expertise in ion channel electrophysiology and project toxicology to move molecules away from this liability through informed choices in molecule design.

Here’s which ion channels are routinely screened in the pharma industry:

91% – hERG
77% – Nav1.5
80% – Cav1.2
53% – Kv7.1

Nav1.5 is cardiac sodium channel, Cav1.2 is cardiac “L-type” calcium channel, Kv7.1 is cardiac lks current

Refine your decision making with a deeper understanding of the potential for effects on cardiac safety to deliver an optimal and de-risked clinical candidate. ApconiX routinely offer sodium and calcium channel assays for a more comprehensive assessment of cardiac liability. On a case-by-case basis we can also deploy other cardiac ion channel assays to suit your needs including cardiac ‘T-type’ calcium channels and Kv1.5 .

Given over 500 years of combined expertise in drug discovery and safety, ApconiX is uniquely positioned to work with your project team to
interpret your data in the context of your drug discovery program.

Flexibility and customer focus

What we need from you:

We only need a few mgs of the compound as a solid or in solution.
We realise not all compounds are soluble in standard organic solvents, e.g. DMSO. Our clients are often looking for ways to increase the solubility of their compounds with a variety of organic and aqueous solvents. We are happy to try a number of solvents which have been validated in our assays.

Apconix
Ic50 Curve Scaled | Apconix

Action of drug, XE991, on Kv4.3 ion channels (Ito current)

What you receive in return:

A report which includes:

  • A 6 point concentration response curve
  • IC₅₀ measured for each compound
  • Methodology, solutions and concentrations used

This is provided within the 4 day turnaround. Each experiment is carried out by and each report is written and reviewed by, an expert electrophysiologist.

hERG FAQs

The human ether-a-go-go related gene (hERG) encodes a cardiac potassium ion channel which controls the electrical activity of the heart and coordinates cardiac action potentials.

Because hERG plays such an important role in cardiac action potentials, inhibition of hERG function by drug compounds can cause heartbeat irregularity with potentially fatal consequences. Because of this, hERG screening is required for all new compounds to ensure they are safe for patients and volunteers.

Good laboratory practice (GLP) dictates that hERG testing is a regulatory requirement for all new compounds before they are administered to humans. Although there is no definitive time for hERG screening, sooner rather than later is always the best option while there is still opportunity to modify the chemistry of the compound and remove any liability or side effects before starting expensive preclinical studies.

The best way to assess hERG activity is via functional hERG screening. Functional screening looks at the activity of the ion channel and provides information on the potency of the compound and therefore how much of a safety risk the compound is to cardiac function.

Binding screening simply looks at the binding of a compound to the hERG channel rather than at activity of the channel itself. Where binding hERG screening gives a binary yes or no answer to the question of ‘does the compound bind with hERG channels’, functional hERG screening quantifies the amount of hERG interaction with the compound giving a more detailed insight to the extent of hERG inhibition by the compound.

The IC50, or half maximal inhibitory concentration, measures how potently a compound inhibits a biological, electrophysiological or biochemical function. The hERG IC50 will depend on the compound being screened and the figure indicates the amount of drug needed to reduce hERG potassium channel function in vitro by 50%.

hERG safety margins are used to evaluate nonclinical cardiac safety by establishing how likely it is that a compound will cause potentially fatal cardiac arrhythmias known as Torsades de Pointes (TdP), or “twisting of the peaks”. Initial hERG safety margins for inducing TdP was set at a hERG IC50 value 30-fold above the therapeutic free plasma concentration (Webster, Leishman, & Walker, 2002) but it has since been suggested to aim for a hERG safety margin between 37- and 50-fold for TdP risk.

Thanks to advances in ion channel screening and development of automated patch clamp technology, ApconiX can turn hERG data around in an average of 4 days with CiPA screening taking an average of 14 days.