Identification and Characterization of a Compound That Protects Cardiac Tissue from Human Ether-à-go-go-related Gene (hERG)-related Drug-induced Arrhythmias

Abstract

Background: Inhibition of the cardiac hERG channel by essential pharmaceuticals is unpredictable and leads to fatal arrhythmias. Results: Pretreatment with a newly identified compound, VU0405601, reduces sensitivity of hERG to inhibition by multiple blockers and prevents arrhythmias. Conclusion: hERG-related arrhythmias are amenable to preventive therapy. Significance: A novel approach at ion channel modulation that impacts drug discovery and safety concerns is outlined.

Modulation of Kv11.1 (hERG) channels by 5‐(((1H–indazol‐5‐yl)oxy)methyl)‐N‐(4‐(trifluoromethoxy)phenyl)pyrimidin‐2‐amine (ITP‐2), a novel small molecule activator

“…In addition to its unique structure, ITP‐2 is distinct in its actions from earlier hERG activators. ITP‐2 selectively increased test pulse currents and decreased tail currents while earlier reported activators increased both pre‐pulse and tail currents (Kang et al, ; Zhou et al, ; Casis et al, ; Zeng et al, ; Hansen et al, ,b; Gordon et al, ; Su et al, ; Gerlach et al, ; Gessner et al, ; Potet et al, ; Zhang et al, ). This is due to reduced rectification in the presence of ITP‐2 resulting in larger test pulse currents and decreased tail currents, similar to the effects caused by a non‐inactivating mutation.…”

“…PD‐307243, NS‐3623, ICA‐105574, ML‐T531 and AZSMO‐23 were shown to produce a shift only in voltage‐dependent inactivation (PD‐307243 at 3 μM +16 mV; NS‐3623 at 30 μM +18 mV; ICA‐105574 at 1 μM > +180 mV; ML‐T531 at 10 μM +28 mV; AZSMO‐23 at 30 μM +74.5 mV) (Hansen et al, ; Gordon et al, ; Gerlach et al, ; Garg et al, ; Zhang et al, ; Mannikko et al, ), while NS‐1643, mallotoxin and KB130015‐induced shift only in voltage‐dependent activation (NS‐1643 at 10 μM −27 mV; mallotoxin at 10 μM −26 mV; KB130015 at 10 μM −16 mV) (Zeng et al, ; Gessner et al, ; Schuster et al, ). A‐935142 and VU0405601 were shown to produce changes in V 1/2 of both voltage‐dependent activation and inactivation, however, V 1/2 changes produced by A‐935142 and VU0405601 even at very high concentrations were smaller in magnitude, compared with those produced by ITP‐2 (Su et al, ; Potet et al, ). With ITP‐2 at 3 μM, the magnitude of effects on V 1/2 of inactivation was similar to ICA‐105574 and the magnitude of effects on V 1/2 of activation was in the same range as that of NS‐1643.…”

“…So far, 12 hERG channel activators have been reported (Kang et al, ; Zhou et al, ; Casis et al, ; Zeng et al, ; Hansen et al, ,b; Gordon et al, ; Su et al, ; Gerlach et al, ; Gessner et al, ; Potet et al, ; Zhang et al, ; Mannikko et al, ). Except for mallotoxin, which is a naturally occurring substance, all the others are synthetic small molecules.…”

Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors

“…Such electrophysiological recordings, utilizing recombinantly expressed hERG channels [14–16] as well as patient-derived cardiomyocytes [17,18], have afforded valuable experimental opportunities to study the potential LQT side effects of small molecules. More recently, the development of high-throughput electrophysiology platforms has facilitated systematic evaluation of hERG inhibition in large compound collections [19,20]. Concurrently, potential global physiological readouts for channel function are suggested by behavioral assays in model organisms such as C.…”

Dissociative States: hERG Channel (Kv11.1) Modulators That Enhance Dissociation of Drugs From Their Blocking Receptor

“…This is in agreement with previous findings that openers/modulators may exert their effect by interacting with the channel at sites separate from the pore, where the class III drugs bind. 7 Interestingly, the authors showcase a clever mean to assay the effect of LUF7244 on hERG channel blockers in a physiological setting by using cultured neonatal rate ventricular myocytes. They used high-resolution optical mapping to record action potentials from cells grown to confluence.…”