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

doi:10.1124/MOLPHARM.120.000048

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^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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 (I_NaL). Here, we took advantage of a high throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (I_NaP) recorded from human induced pluripotent stem cell-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with 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 I_NaPin a frequencydependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB of I_NaP(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 with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

Original language	English (US)
Pages (from-to)	540-547
Number of pages	8
Journal	Molecular pharmacology
Volume	98
Issue number	5
DOIs	https://doi.org/10.1124/MOLPHARM.120.000048
State	Published - Nov 1 2020

Funding

Dr. Potet is a paid consultant for Praxis Precision Medicines, Inc. Dr. George serves on a scientific advisory board for Amgen, Inc. and received previous grant support from Merck and Co., Gilead Sciences, Inc., and Praxis Precision Medicines, Inc. An earlier version of this paper appears in bioRxiv under the DOI: 10.1101/ 2020.05.08.084350. This work was funded in part by a grant from Fondation Leducq and through research investments by the Northwestern Medicine Catalyst Fund. https://doi.org/10.1124/molpharm.120.000048. s This article has supplemental material available at molpharm. aspetjournals.org.

ASJC Scopus subject areas

Molecular Medicine
Pharmacology

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10.1124/MOLPHARM.120.000048

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@article{59d69d078a194407aced5d54f1551ec6,

title = "GS-967 and eleclazine block sodium channels in human induced pluripotent stem cell-derived cardiomyocytes",

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 high 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-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with 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 INaPin a frequencydependent 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 with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.",

author = "Franck Potet and Egecioglu, {Defne E.} and Burridge, {Paul W.} and George, {Alfred L.}",

note = "Funding Information: Dr. Potet is a paid consultant for Praxis Precision Medicines, Inc. Dr. George serves on a scientific advisory board for Amgen, Inc. and received previous grant support from Merck and Co., Gilead Sciences, Inc., and Praxis Precision Medicines, Inc. An earlier version of this paper appears in bioRxiv under the DOI: 10.1101/ 2020.05.08.084350. This work was funded in part by a grant from Fondation Leducq and through research investments by the Northwestern Medicine Catalyst Fund. https://doi.org/10.1124/molpharm.120.000048. s This article has supplemental material available at molpharm. aspetjournals.org. Publisher Copyright: {\textcopyright} 2020 American Society for Pharmacology and Experimental Therapy. All rights reserved.",

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AU - Burridge, Paul W.

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N1 - Funding Information: Dr. Potet is a paid consultant for Praxis Precision Medicines, Inc. Dr. George serves on a scientific advisory board for Amgen, Inc. and received previous grant support from Merck and Co., Gilead Sciences, Inc., and Praxis Precision Medicines, Inc. An earlier version of this paper appears in bioRxiv under the DOI: 10.1101/ 2020.05.08.084350. This work was funded in part by a grant from Fondation Leducq and through research investments by the Northwestern Medicine Catalyst Fund. https://doi.org/10.1124/molpharm.120.000048. s This article has supplemental material available at molpharm. aspetjournals.org. Publisher Copyright: © 2020 American Society for Pharmacology and Experimental Therapy. All rights reserved.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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 high 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-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with 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 INaPin a frequencydependent 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 with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

AB - 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 high 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-derived cardiomyocytes. We compared the effects of GS-967 and eleclazine with 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 INaPin a frequencydependent 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 with the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the higher association rates and moderate unbinding rate of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

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GS-967 and eleclazine block sodium channels in human induced pluripotent stem cell-derived cardiomyocytes

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