Dealing with hERG liabilities early: Diverse approaches to an important goal in drug development

Abstract

In drug development, early recognition of a potential for blocking the human ether-a-go-go related gene (hERG) channels is perhaps the best way to avoid later disappointment when QT interval prolongation shows up in clinical trials. Knowledge of the hERG blocking liability offers the chance to modify the molecule to reduce, or even eliminate, this unwanted activity and lack of success in such modification is a good reason to stop further development of the molecule. In this issue of the BJP, different methods for early detection of hERG channel blocking liability are discussed by Pollard et al. One attractive approach is widespread screening of molecules at a very early stage of research to detect compounds with this liability and thereby eliminate them. There are now several methodologies available that offer hERG channel testing on a high-throughput format but entail a diverse selection of direct and indirect readouts of hERG channel blocking activity and all are subject to practical limitations that also need to be considered prior to investing in a particular experimental approach. The approach selected, if any, should reflect the resources and expertise available. In any case, it is essential to be aware of the experimental limitations and potential inaccuracies that are inherent to each approach. © 2010 The British Pharmacological Society.