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Voltage-gated potassium 11.1 (K v 11.1) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug-mediated K v 11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal K v 11.1 forward trafficking and thus reduce functional K v 11.1 channel densities. Although class III antiarrhythmics, e.g., dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use because of their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a K v 11.1 allosteric modulator/activator, to rescue K v 11.1 trafficking and produce functional K v 11.1 current. LUF7244 treatment by itself did not disturb or rescue wild type (WT) or G601S-K v 11.1 trafficking, as shown by Western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT K v 11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S-K v 11.1 cells, dofetilide (10 μM) or dofetilide + LUF7244 (10 + 5 μM) also restored K v 11.1 trafficking, as demonstrated by Western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased I Kv 11.1 despite the presence of dofetilide (1 μM) in WT K v 11.1 cells. In G601S-expressing cells, long-term treatment (24-48 hour) with LUF7244 (10 μM) and dofetilide (1 μM) increased I Kv11.1 compared with nontreated or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues K v 11.1 trafficking and produces functional I Kv11.1 Thus, combined administration of LUF7244 and an I Kv11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced K v 11.1 trafficking defects. SIGNIFICANCE STATEMENT: Decreased levels of functional K v 11.1 potassium channel at the plasma membrane of cardiomyocytes prolongs action potential repolarization, which associates with cardiac arrhythmia. Defective forward trafficking of K v 11.1 channel protein is an important factor in acquired and congenital long QT syndrome. LUF7244 as a negative allosteric modulator/activator in combination with dofetilide corrected both congenital and acquired K v 11.1 trafficking defects, resulting in functional K v 11.1 current., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background and Purpose: K v 11.1 (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 K v 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model., Experimental Approach: LUF7244 was tested in vitro for (a) increasing human I Kv11.1 and canine I Kr 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 Results: LUF7244 (0.5-10 μM) concentration dependently increased I Kv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on I KIR2.1 , I Nav1.5 , I Ca-L , and I Ks , doubled I Kr , 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 Implications: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of K v 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)