Cardiac ion channel safety profiling on the IonWorks Quattro automated patch clamp system.
The normal electrophysiologic behavior of the heart is determined by the integrated activity of specific cardiac ionic currents. Mutations in genes encoding the molecular components of individual cardiac ion currents have been shown to result in multiple cardiac arrhythmia syndromes. Presently, 12 genes associated with inherited long QT syndrome (LQTS) have been identified, and the most common mutations are in the hKCNQ1 (LQT1, Jervell and Lange-Nielson syndrome), hKCNH2 (LQT2), and hSCN5A (LQT3, Brugada syndrome) genes. Several drugs have been withdrawn from the market or received black box labeling due to clinical cases of QT interval prolongation, ventricular arrhythmias, and sudden death. Other drugs have been denied regulatory approval owing to their potential for QT interval prolongation. Further, off-target activity of drugs on cardiac ion channels has been shown to be associated with increased mortality in patients with underlying cardiovascular diseases. Since clinical arrhythmia risk is a major cause for compound termination, preclinical profiling for off-target cardiac ion channel interactions early in the drug discovery process has become common practice in the pharmaceutical industry. In the present study, we report assay development for three cardiac ion channels (hKCNQ1/minK, hCa(v)1.2, and hNa(v)1.5) on the IonWorks Quattro™ system. We demonstrate that these assays can be used as reliable pharmacological profiling tools for cardiac ion channel inhibition to assess compounds for cardiac liability during drug discovery.
Center for Proteomic Chemistry, Novartis Institutes for BioMedical Sciences Inc., Cambridge, Massachusetts 02139, USA.
Xueying
X
Cao
Yan Tony
YT
Lee
Mats
M
Holmqvist
Yingxin
Y
Lin
Yucheng
Y
Ni
Dmitri
D
Mikhailov
Haiyan
H
Zhang
Christopher
C
Hogan
Liping
L
Zhou
Qiang
Q
Lu
Mary Ellen
ME
Digan
Laszlo
L
Urban
Gül
G
Erdemli
D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery; D004562:Electrocardiography; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000502:physiology; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015203:Reproducibility of Results; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C419385:L-type calcium channel alpha(1C); D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels