title: Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds.
abstract: Unintended inhibition of the cardiac potassium channel human ether-a-go-go-related gene (hERG) is considered the main culprit in drug-induced arrhythmias known as torsades de pointes. Electrophysiology is the most reliable in vitro screening method for identifying potential cardiac hERG liabilities, but only the recent advent of planar electrode-based voltage clamp electrophysiology promises sufficient throughput to support the drug testing needs of most drug discovery programs. We have assessed the reliability of this new format of the voltage clamp technology in measuring the activity of small molecules on the hERG channel. Based on the results herein of a screening against a panel of well-characterized hERG-active and -inactive molecules, we demonstrate that planar electrode electrophysiology, utilizing the Sealchip and PatchXpress technology platform (AVIVA Biosciences Corp., San Diego, CA), is comparable to traditional electrophysiology based on glass micropipettes in its reliability and data content. The new technology will allow significantly higher throughput and more thorough testing of pharmaceutical compounds.
authors.affiliation: AVIVA Biosciences Corporation, 11180 Roselle Street, San Diego, CA 92121, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Tao
authors.forename: David
authors.initials: D
authors.lastname: Santa Ana
authors.forename: António
authors.initials: A
authors.lastname: Guia
authors.forename: Mingxian
authors.initials: M
authors.lastname: Huang
authors.forename: Joseph
authors.initials: J
authors.lastname: Ligutti
authors.forename: George
authors.initials: G
authors.lastname: Walker
authors.forename: Khachonesine
authors.initials: K
authors.lastname: Sithiphong
authors.forename: Florence
authors.initials: F
authors.lastname: Chan
authors.forename: Tao
authors.initials: T
authors.lastname: Guoliang
authors.forename: Zoya
authors.initials: Z
authors.lastname: Zozulya
authors.forename: Steve
authors.initials: S
authors.lastname: Saya
authors.forename: Rick
authors.initials: R
authors.lastname: Phimmachack
authors.forename: Charles
authors.initials: C
authors.lastname: Sie
authors.forename: Julian
authors.initials: J
authors.lastname: Yuan
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghetti
mesh_terms: D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D018408:Patch-Clamp Techniques / Q000379:methods; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D000638:Amiodarone