Key result
Pretreatment with the Kv11.1 allosteric modulator LUF7244 prevented astemizole- or sertindole-induced action potential prolongation and early afterdepolarizations in vitro.
Why the study?
Does allosteric modulation of the Kv11.1 channel prevent drug-induced ventricular arrhythmias in preclinical models?
Does allosteric modulation of the Kv11.1 channel prevent drug-induced ventricular arrhythmias in preclinical models?
Allosteric modulation of the Kv11.1 (hERG) channel with LUF7244 prevents drug-induced proarrhythmic changes in vitro, suggesting a potential pharmacological strategy to mitigate the proarrhythmic risk of unintended Kv11.1 blockers.
May warrant further Kv11.1 modulator development; leaves open clinical translation for drug-induced proarrhythmia prevention.
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 In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia.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. METHODS AND 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.
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Yu et al. (2016) studied Drug-induced ventricular arrhythmias. Kv11.1 allosteric modulators (LUF7244) vs. Typical blockers alone (astemizole, sertindole) was evaluated on Prevention of proarrhythmic effects (action potential duration prolongation and early afterdepolarizations). Pretreatment with the Kv11.1 allosteric modulator LUF7244 prevented astemizole- or sertindole-induced action potential prolongation and early afterdepolarizations in vitro.
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