Identification and Characterization of a Compound That Protects Cardiac Tissue from Human Ether-à-go-go-related Gene (hERG)-related Drug-induced Arrhythmias
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 unintended hERG inhibition by diverse pharmaceuticals can cause arrhythmias and sudden cardiac death. We hypothesized that a small molecule that...
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Published in: | The Journal of biological chemistry Vol. 287; no. 47; pp. 39613 - 39625 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
United States
Elsevier Inc
16-11-2012
American Society for Biochemistry and Molecular Biology |
Subjects: | |
Online Access: | Get full text |
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Summary: | 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 unintended hERG inhibition 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.
Background: Inhibition of the cardiac hERG channel by essential pharmaceuticals is unpredictable and leads to fatal arrhythmias.
Results: Pretreatment with a newly identified compound, VU0405601, reduces sensitivity of hERG to inhibition by multiple blockers and prevents arrhythmias.
Conclusion: hERG-related arrhythmias are amenable to preventive therapy.
Significance: A novel approach at ion channel modulation that impacts drug discovery and safety concerns is outlined. |
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Bibliography: | Supported in part by a Scientist Development Grant from the American Heart Association. |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M112.380162 |