Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias

Franck Potet, Amanda N. Lorinc, Sebastien Chaigne, Corey R. Hopkins, Raghav Venkataraman, Svetlana Z. Stepanovic, L. Michelle Lewis, Emily Days, Veniamin Y. Sidorov, Darren W. Engers, Beiyan Zou, David Afshartous, Alfred L. George, Courtney M. Campbell, Jeffrey R. Balser, Min Li, Franz J. Baudenbacher, Craig W. Lindsley, C. David Weaver, Sabina Kupershmidt

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The human Ether-à-go-go-related gene (hERG)-encoded K+ current, IKr is essential for cardiac repolarization but is also a source of cardiotoxicity because unintendedhERGinhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that diminishes IKr block by a known hERG antagonist would constitute a first step toward preventing hERG-related arrhythmias and facilitating drug discovery. Using a high-throughput assay, we screened a library of compounds for agents that increase the IC70 of dofetilide, a well characterized hERG blocker. One compound, VU0405601, with the desired activity was further characterized. In isolated, Langendorff-perfused rabbit hearts, optical mapping revealed that dofetilide-induced arrhythmias were reduced after pretreatment with VU0405601. Patch clamp analysis in stable hERG-HEK cells showed effects on current amplitude, inactivation, and deactivation. VU0405601 increased the IC50 of dofetilide from 38.7 to 76.3 nM. VU0405601 mitigates the effects of hERG blockers from the extracellular aspect primarily by reducing inactivation, whereas most clinically relevant hERG inhibitors act at an inner pore site. Structure-activity relationships surrounding VU0405601 identified a 3-pyridiyl and a naphthyridine ring system as key structural components important for preventing hERG inhibition by multiple inhibitors. These findings indicate that small molecules can be designed to reduce the sensitivity of hERG to inhibitors.

Original languageEnglish (US)
Pages (from-to)39613-39625
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number47
DOIs
StatePublished - Nov 16 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Potet, F., Lorinc, A. N., Chaigne, S., Hopkins, C. R., Venkataraman, R., Stepanovic, S. Z., Lewis, L. M., Days, E., Sidorov, V. Y., Engers, D. W., Zou, B., Afshartous, D., George, A. L., Campbell, C. M., Balser, J. R., Li, M., Baudenbacher, F. J., Lindsley, C. W., Weaver, C. D., & Kupershmidt, S. (2012). Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias. Journal of Biological Chemistry, 287(47), 39613-39625. https://doi.org/10.1074/jbc.M112.380162