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GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes

View ORCID ProfileFranck Potet, Defne E. Egecioglu, View ORCID ProfilePaul W. Burridge, View ORCID ProfileAlfred L. George Jr.
doi: https://doi.org/10.1101/2020.05.08.084350
Franck Potet
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Defne E. Egecioglu
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Paul W. Burridge
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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Alfred L. George Jr.
1Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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  • For correspondence: al.george@northwestern.edu
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ABSTRACT

GS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (INaL). Here, we took advantage of a throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (INaP) recorded from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We compared GS-967 and eleclazine to the antiarrhythmic drug lidocaine, the prototype INaL inhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction of INaP in a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of INaP (IC50=0.07 and 0.6 μM, respectively) than ranolazine (7.8 μM), lidocaine (133.5 μM) and lacosamide (158.5 μM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared to the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the significantly higher association rates (KON) and moderate unbinding rate (KOFF) of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

SIGNIFICANCE STATEMENT We investigated the molecular pharmacology of GS-967 and eleclazine on sodium channels in human induced pluripotent stem cell derived cardiomyocytes using a high throughput automated electrophysiology platform. Sodium channel inhibition by GS-967 and eleclazine has unique features including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy.

Competing Interest Statement

A.L.G. received a research grant from Praxis Precision Medicines, Inc for an unrelated research project involving one of the compounds studied in this manuscript (GS-967).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 10, 2020.
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GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Franck Potet, Defne E. Egecioglu, Paul W. Burridge, Alfred L. George Jr.
bioRxiv 2020.05.08.084350; doi: https://doi.org/10.1101/2020.05.08.084350
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GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Franck Potet, Defne E. Egecioglu, Paul W. Burridge, Alfred L. George Jr.
bioRxiv 2020.05.08.084350; doi: https://doi.org/10.1101/2020.05.08.084350

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