title: HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk.
abstract: BACKGROUND
  Direct block of I(Kr) by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current I(Kr), however. We have shown recently that two drugs in clinical use do not block hERG but produce long QT syndrome (LQTS) and TdP by inhibiting trafficking of hERG to the cell surface. To address the need for an inexpensive, rapid, and comprehensive assay to predict both types of hERG risk early in the drug development process, we have developed a novel antibody-based chemiluminescent assay called HERG-Lite.
  
  
  METHODS
  HERG-Lite monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers.
  
  
  RESULTS
  HERG-Lite correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition).
  
  
  CONCLUSIONS
  HERG-Lite is the most comprehensive assay available for predicting drug-induced hERG risk. It accurately predicts both channel blockers and trafficking inhibitors in a rapid, cost-effective manner and is a valuable non-clinical assay for drug safety testing.
authors.affiliation: ChanTest Inc, ChanXpress Inc, Cleveland, OH, 44128, USA. bwible@chantest.com
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wible
authors.forename: Peter
authors.initials: P
authors.lastname: Hawryluk
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Kuryshev
authors.forename: Glenn
authors.initials: G
authors.lastname: Kirsch
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Brown
mesh_terms: D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008163:Luminescent Measurements; D004364:Pharmaceutical Preparations / Q000145:classification; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000145:classification; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011237:Predictive Value of Tests; D016171:Torsades de Pointes / Q000139:chemically induced*
chemical_list: D004364:Pharmaceutical Preparations; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated