Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds.
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.
Tao
Huimin
H
AVIVA Biosciences Corporation, 11180 Roselle Street, San Diego, CA 92121, USA.
Santa Ana
David
D
Guia
António
A
Huang
Mingxian
M
Ligutti
Joseph
J
Walker
George
G
Sithiphong
Khachonesine
K
Chan
Florence
F
Guoliang
Tao
T
Zozulya
Zoya
Z
Saya
Steve
S
Phimmachack
Rick
R
Sie
Charles
C
Yuan
Julian
J
Wu
Lei
L
Xu
Jia
J
Ghetti
Andrea
A
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*
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