title: Identification and characterization of a compound that protects cardiac tissue from human Ether-à-go-go-related gene (hERG)-related drug-induced arrhythmias.
abstract: The human Ether-à-go-go-related gene (hERG)-encoded K(+) current, I(Kr) 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 I(Kr) 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 IC(70) 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 IC(50) 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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University, Nashville, Tennessee 37232, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Potet
authors.forename: Amanda N
authors.initials: AN
authors.lastname: Lorinc
authors.forename: Sebastien
authors.initials: S
authors.lastname: Chaigne
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: Raghav
authors.initials: R
authors.lastname: Venkataraman
authors.forename: Svetlana Z
authors.initials: SZ
authors.lastname: Stepanovic
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Emily
authors.initials: E
authors.lastname: Days
authors.forename: Veniamin Y
authors.initials: VY
authors.lastname: Sidorov
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.forename: Beiyan
authors.initials: B
authors.lastname: Zou
authors.forename: David
authors.initials: D
authors.lastname: Afshartous
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Campbell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Balser
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Baudenbacher
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Sabina
authors.initials: S
authors.lastname: Kupershmidt
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D010627:Phenethylamines / Q000009:adverse effects* / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009124:Muscle Proteins; D009287:Naphthyridines; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C578328:VU0405601; C063533:dofetilide