Inhibitors of hERG Channel Trafficking

Direct blockade of the cardiac potassium channel encoded by the KCNH2 gene, the human ether-a-go-go related gene (hERG) product, has been recognized for some time as a potential liability that is typically assessed by electrophysiological testing during preclinical profiling of drug candidates. However, inhibition of hERG protein trafficking has emerged as a potential mechanism of interfering with channel function that can only be detected by a very different screening paradigm that relies on extended incubation of hERG-expressing cells with candidate compounds. In this chapter, the background biochemical pharmacology underlying hERG protein trafficking is discussed and those compounds that have been shown to interfere with hERG channel expression on the cell surface together with insights into their mechanism of action are summarized. Assays that have recently been developed to detect hERG trafficking inhibitors are also described.