title: Allosteric Modulation of Kv11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias.
abstract: BACKGROUND
  Ventricular arrhythmias as a result of unintentional blockade of the Kv11.1 (hERG [human ether-à-go-go-related gene]) channel are a major safety concern in drug development. In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia. Here, we investigated whether the proarrhythmic risk of existing drugs could be reduced by Kv11.1 allosteric modulators.
  
  
  RESULTS
  Using [(3)H]dofetilide-binding assays with membranes of human Kv11.1-expressing human embryonic kidney 293 cells, 2 existing compounds (VU0405601 and ML-T531) and a newly synthesized compound (LUF7244) were found to be negative allosteric modulators of dofetilide binding to the Kv11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The Kv11.1 affinities of typical blockers (ie, dofetilide, astemizole, sertindole, and cisapride) were significantly decreased by LUF7244. Treatment of confluent neonatal rat ventricular myocyte (NRVM) monolayers with astemizole or sertindole caused heterogeneous prolongation of action potential duration and a high incidence of early afterdepolarizations on 1-Hz electric point stimulation, occasionally leading to unstable, self-terminating tachyarrhythmias. Pretreatment of NRVMs with LUF7244 prevented these proarrhythmic effects. NRVM monolayers treated with LUF7244 alone displayed electrophysiological properties indistinguishable from those of untreated NRVM cultures. Prolonged exposure of NRVMs to LUF7244 or LUF7244 plus astemizole did not affect their viability, excitability, and contractility as assessed by molecular, immunological, and electrophysiological assays.
  
  
  CONCLUSIONS
  Allosteric modulation of the Kv11.1 channel efficiently suppresses drug-induced ventricular arrhythmias in vitro by preventing potentially arrhythmogenic changes in action potential characteristics, raising the possibility to resume the clinical use of unintended Kv11.1 blockers via pharmacological combination therapy.
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Yu
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Jacobus P D
authors.initials: JP
authors.lastname: van Veldhoven
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schalij
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.).
authors.forename: Daniël A
authors.initials: DA
authors.lastname: Pijnappels
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.). l.h.heitman@lacdr.leidenuniv.nl a.a.f.de_vries@lumc.nl.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.affiliation: From the Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (Z.Y., J.P.D.v.V., A.P.I., L.H.H.); Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands (J.L., M.J.S., D.A.P., A.A.F.d.V.); and ICIN-Netherlands Heart Institute, Utrecht, The Netherlands (J.L., A.A.F.d.V.). l.h.heitman@lacdr.leidenuniv.nl a.a.f.de_vries@lumc.nl.
authors.forename: Antoine A F
authors.initials: AA
authors.lastname: de Vries
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000633:toxicity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D012313:RNA
keywords: arrhythmias, cardiac; cardiotoxicity; cell culture techniques; myocytes, cardiac; potassium voltage-gated channel, subfamily H, member 2; radioligand assay; voltage-sensitive dye imaging