HERG Potassium Channel Interaction

Toxicological events and cardiovascular toxicity are of particular concern to the regulatory authorities. Torsade de points (TdP), an example of such adverse cardiovascular responses, is specifically monitored by the FDA. TdP results from a 

Efforts to predict the risk of potential QT prolongation over the last decade have resulted in the number of preclinical in vitro and in vivo methodologies. In vitro methods to predict QT liabilities range from simple recombinant cellular assays to disaggregated cells, isolated tissues and perfused heart preparations.  

Recently predictive in silico modeling for hERG channel blockers has been described. Different approaches have aimed primarily at fdtering out potential hERG channel blockers in the context of combinatorial and virtual libraries and to elucidate structure-activity relationships. These new computational methods may predict trends, but are not as yet sufficiently precise to make valid predictions. 

The number of useful biomarkers to predict neurotoxicity, hepatotoxicity or cardiovascular toxicity is still rather limited and they are not yet well established as tools in pharmaceutical laboratories. Even though some decent correlations between biomarkers and toxicological events have been demonstrated, a significant amount of validation work still has to be performed. Eor example, while natriuretic peptides and troponin can be clinical markers for cardiovascular toxicity, preclinical use in 

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Safety pharmacology In vitro assays can test for hERG potassium channel interaction early in discovery, with ox vivo and in vivo assays being applied later in discovery. HCA assays are being developed for in vitro assessments of cardiac toxicity potential... 

Cui, J., Kagan, A., Qin, D., Mathew, J., Melman, Y.F. and McDonald, T.V. (2001) Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2. The Journal of Biological Chemistry, 276, 17244-17251. 

Testai L, Bianucci AM, Massarelli I, Breschi MC, Martinotti E, Calderone V. Torsadogenic cardiotoxicity of antipsychotic drugs A structural feature, potentially involved in the interaction with cardiac HERG potassium channels. Curr Med Chem 2004 11 2691-706. 

Kang J, Chen XL, Wang L, et al. Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQTl/minK and HERG. / Pharmacol Ex The. 2001 299(l) 290-296. 

Avoid interaction with hERG potassium ion channel (IC50) >10 pM... 

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