SBIR-STTR Award

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 an example of frequent unwanted drug interactions; block of hERG can predispose individuals to cardiac arrhythmias. Given the dual nature of ion channel targets, there is a need for high throughput assays that address the therapeutic potential as well as the drug safety issue. ChanTest, an ion channel company dedicated to providing technology services to the biopharmaceutical industry for drug safety testing and drug discovery involving ion channels, is developing novel high throughput screens that can address both needs. These proprietary assays monitor the level of expression of ion channels using an antibody-based chemiluminescent reaction. The goals of this proposal are to develop assays using the hERG potassium channel for two purposes: 1) HTXpress: high throughput screening of diverse chemical libraries for compounds which either increase or decrease hERG expression without affecting the kinetic properties of the channel, and 2) hERG-Lite: high throughput drug safety screening to identify drugs which block hERG using increased surface expression of mutant hERG channels as a biosensor for block. For HTXpress, the specific aim of this proposal is to optimize the assay by screening a structurally diverse chemical library of over 800 compounds. The identification of ion channel expression modulators, i.e. novel agonists and antagonists, is an untapped area of drug development and can be easily applied to channels other than hERG. With respect to hERG-Lite, the goal is to validate the use of this assay as a rapid safety test for hERG block. Eighty drugs (half known hERG blockers and half nonblockers) will be assayed for their behavior in the expression assay. Their potencies and rank order will be compared to hERG block assayed by standard electrophysiological measurements. The goal is to introduce hERG-Lite to the pharmaceutical industry as a rapid, inexpensive, and sensitive screen for hERG safety testing early in drug development.

Thesaurus Terms:
drug discovery /isolation, high throughput technology, ion channel blocker, potassium channel, technology /technique development biosensor, chemical registry /resource, drug screening /evaluation biotechnology, enzyme linked immunosorbent assay, tissue /cell culture, voltage /patch clamp

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