LUF7244, an allosteric modulator/activator of K_v11.1 channels, counteracts dofetilide‐induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model

Abstract

Background and PurposeKv11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model.Experimental ApproachLUF7244 was tested in vitro for (a) increasing human IKv11.1 and canine IKr and (b) decreasing dofetilide‐induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block.Key ResultsLUF7244 (0.5–10 μM) concentration dependently increased IKv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on IKIR2.1, INav1.5, ICa‐L, and IKs, doubled IKr, shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide‐induced early afterdepolarizations. LUF7244 (2.5 mg·kg−1·15 min−1) in dogs with sinus rhythm was not proarrhythmic and shortened, non‐significantly, repolarization parameters (QTc: −6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide‐induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block.Conclusions and ImplicationsLUF7244 counteracted dofetilide‐induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.

An Update on the Structure of hERG

“…LUF7244 is another hERG activator reported also to act by attenuating rapid inactivation (Qile et al, 2019), that suppresses binding of hERG inhibitors (cisapride, astemizole, dofetililde and sertindole (Yu et al, 2016)). The potential of hERG activators as therapeutics to counteract the effects of drug-induced LQTS is shown by the recent demonstration of suppression of dofetilide-induced torsades de pointes arrhythmia in a dog model (Qile et al, 2019) by this activator.…”

“…LUF7244 is another hERG activator reported also to act by attenuating rapid inactivation (Qile et al, 2019), that suppresses binding of hERG inhibitors (cisapride, astemizole, dofetililde and sertindole (Yu et al, 2016)). The potential of hERG activators as therapeutics to counteract the effects of drug-induced LQTS is shown by the recent demonstration of suppression of dofetilide-induced torsades de pointes arrhythmia in a dog model (Qile et al, 2019) by this activator. LUF7244 can be docked into the hERG pore domain of the cryo-EM structure between two subunits and partly occupying a hydrophobic pocket in a manner that might overlap with the binding site for dofetilide (Qile et al, 2019) which is expected to lie largely in the K + permeation pathway below the selectivity filter (Kamiya et al, 2006).…”

“…The potential of hERG activators as therapeutics to counteract the effects of drug-induced LQTS is shown by the recent demonstration of suppression of dofetilide-induced torsades de pointes arrhythmia in a dog model (Qile et al, 2019) by this activator. LUF7244 can be docked into the hERG pore domain of the cryo-EM structure between two subunits and partly occupying a hydrophobic pocket in a manner that might overlap with the binding site for dofetilide (Qile et al, 2019) which is expected to lie largely in the K + permeation pathway below the selectivity filter (Kamiya et al, 2006). On the other hand, [ 3 H]dofetilide binding displacement by LUF7244 indicates that this activator is an allosteric modulator of dofetilide binding with a distinct (non-overlapping) binding site (Yu et al, 2016), and so this activator might constitute an additional example where the suppression of inactivation also suppresses inactivationassociated conformational changes below the selectivity filter that optimise high-affinity inhibitor binding.…”

Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients

“…However, they could lead to abnormal shortening of the QT interval and increase the risk for deadly arrhythmias like ventricular fibrillation. Qile and colleagues (2020) determined whether the functional expression of Class 2 LQT2 Kv11.1 channels could be increased by culturing cells in I Kr blockers and the I Kr activator LUF7244 [58,59]. LUF7244 is an allosteric I Kr activator that counteracts I Kr blocker induced arrhythmias in dogs.…”

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

“…Delayed rectifier I Kr loss-of-function is associated with long QT syndrome type 2 and cardiac arrhythmia [69]. A number of compounds have been developed and tested in animal models for antiarrhythmic properties [70][71][72][73]. Currently, these activators mainly function to enhance channel kinetics resulting in increased potassium current.…”