hERG Channel Drug Candidate Screening

CDI's GLP-Compliant and Non-GLP Laboratory Services

Identifying hERG channel block by candidate molecules is a crucial element of drug development. Cellular Dynamics International, Inc. (CDI) offers definitive and reliable results demonstrating potential interactions between hERG channels and candidate pharmaceuticals through our GLP-compliant and non-GLP assays.

Since CDI founder Dr. Craig January pioneered the HEK293 hERG screening test in 1997, several important drugs have been removed from the market due to their blocking effect on cardiac hERG channels, including Seldane (1998), Raxar (1999), Hismanal (1999), and Propulsid (2000). These drugs, and other drug candidates, were found to induce long QT syndrome (LQTS) in certain individuals and increase the potential for sudden death from arrhythmia. Many more drugs have received black box warnings for the same effect.

in vitro hERG Channel Assays

CDI’s hERG screening process uses the definitive, tight-seal, whole-cell voltage clamp technique to determine the concentration-response relation for Test Article block of hERG channels stably expressed in HEK293 cells. GLP-compliant assays are performed at near physiological temperatures, since some drugs have been found to exhibit different hERG blocking characteristics at room temperature and at near physiological temperature. Non-GLP assays mimic the GLP-compliant assay but are performed at room temperature. Furthermore, to evaluate relative hERG block among candidate molecules, multiple compounds can be tested at a single concentration to produce a relative ranking of hERG channel block.

Reliable Results

Concentration-response data showing greater than 50% block of channel activity is fit with the Hill equation to derive the actual IC₅₀ as well as the coefficient of the relation. While CDI recommends the standard IC₅₀ assay for the most definitive determination of hERG block, other test protocols are available as well.

GLP-compliant lab results include:

• Data and reports undergo full scientific review and GLP-compliant QA oversight. The report also includes the approval of Dr. Craig January, an expert and pioneer of the hERG assay.
• All CDI GLP-compliant services adhere to FDA regulations, 21 C.F.R. Part 58.
• Adherance to OECD and MHLW regulations can be requested.
• Assistance in post-study interpretation is available.

Non-GLP results include a GLP-like report with full scientific review.

hERG Channel Assay Specifications
		GLP-Compliant Lab Services	Non-GLP Lab Services
	Assay	Gold-standard voltage clamp assay using hERG channels heterologously expressed in HEK293 cells.
	Concentrations	Four drug concentraitons bracketing 50% block.
	Endpoint	IC50 determination from hERG tail current.
	Controls	Positive and negative controls are used in each assay to monitor experimental conditions.
	Replicates/Concentration	Four	Three
	Temperature	Near physiological temperature	Room temperature
	Dose Solution Sampling	Automatically included, for homogeneity and concentration verification.	Upon request