Research Project
6736717
DESCRIPTION (provided by applicant): 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.
