Ion channels comprise 10-20 percent of known drug targets for diseases including cardiac arrhythmias, stroke, hypertension, heart failure, asthma, cystic fibrosis, epilepsy, migraine, mental disorders, muscular dystrophy, and cancer. While ion channels provide important therapeutic targets, they are often the focal point of unwanted drug interactions leading to potentially serious side effects. The cardiac potassium channel hERG is the most common target of undesired drug interactions; block of hERG can predispose individuals to cardiac arrhythmias, long QT syndrome, and sudden cardiac death. The FDA recommends that all drugs being considered for investigational new drug applications (IND) be tested for their effects on the hERG potassium channel in preclinical studies. Due to the increasing costs of drug development, it is crucial that pharmaceutical companies test their compounds for hERG liability at early stages in the process. Recent evidence indicates that drug-induced hERG liability can arise not just from direct block of the channel, but by inhibiting the movement of the hERG channel from its intracellular site of synthesis to the cell surface. This trafficking inhibition results in fewer functional channels at the cell surface. Arsenic trioxide and pentamidine, both of which are in clinical use today, act in this fashion and have been linked to long QT syndrome. None of the current methods for determining hERG liability are able to detect trafficking inhibitors. ChanXpress, Inc. has developed a novel safety screen for hERG liability that is the most comprehensive available. It detects both channel blockers and trafficking inhibitors using a proprietary technology that monitors surface expression of hERG channels using an antibody-based, chemiluminescent assay. In Phase II, we will compile a hERG liability database of 880 compounds that includes results from hERG-Lite screening along with patch clamp and Western blot data. We will automate the HERG-Lite assay at ChanXpress so that it can be offered to more clients with a higher throughput than is currently available. Finally, ChanXpress will develop a HERG-Lite kit that includes cell line, reagent, and instrumentation options so that clients are able to perform that assay at their own facility. The combination of speed, low cost, high throughput, and comprehensive hERG liability predictions position HERG-Lite as the premier assay for hERG liability screening early in the drug development process. ? ? ? ? ?
