Cellular Dynamics International, Inc. (CDI) offers a new, definitive and reliable in vitro test to detect drug candidates that interfere with trafficking of the hERG channel protein from its intracellular synthesis sites to the plasma membrane.

Introduction

Assays for hERG block of drug candidates are a crucial element of drug development.  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, as well as other drug candidates, have been 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. 

Assessing Drug Inhibition of hERG Trafficking

In addition to acute block of hERG channel, emerging scientific studies by Dr. Craig January and others are documenting a chronic effect on hERG channels by pharmaceuticals through a mechanism different from hERG block.  This mechanism is the inhibition of hERG protein trafficking from the endoplasmic reticulum to the cell membrane.  Unlike acute interactions with drugs, where functional hERG channel activity is reduced through direct block of channels by a small molecule, inhibition of protein trafficking reduces the amount of functional hERG channel activity by preventing channel insertion into the plasma membrane.  This phenomenon has been observed across drug classes and occurs in both little used and widely prescribed pharmaceuticals.

In addition, this phenomenon of hERG trafficking disruption can also lead to LQTS in susceptible patients.  Cellular Dynamics International’s hERG trafficking assay has been designed in consultation with Dr. January, who first identified hERG trafficking as a contributor to clinical LQTS.   

CDI’s Definitive Test

CDI offers a reliable, non-GLP biochemical assay to assess the potential for test compound inhibition of hERG trafficking.  CDI’s hERG Channel Trafficking Assay specifications include:

• A Western blot based assay
• Using the hERG channel gene expressed in HEK293 cells
• Minimum of 3 drug concentrations tested

Advantages

CDI Services for Drug Safety Screening & Discovery

• Accurate assay for hERG trafficking
• Accelerated drug development in key therapeutic target areas
• Extensive experience with drug-induced effects on ion channels
• Reliable screening results
• Rapid turnaround
  

Results

Positive and negative controls are used in each assay to monitor experimental conditions.  Assistance is provided in analyzing results. 

References

Eckhardt LL, Rajamani S, January CT.  2005.  Protein trafficking abnormalities: A new mechanism in drug-induced long QT syndrome.  Br J Pharmacol.  145:   3-4.

Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson CL, Holzem KM, Delisle BP, Anson BD, Makielski JC, January CT.  2006. Drug-induced long QT syndrome:  hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine  Br J Pharmacol.  [In Press].