<scp>K<sub>v</sub>11.1</scp> (<scp>hERG</scp>)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical <scp>K<sub>v</sub>11.1</scp> (<scp>hERG</scp>) inhibitors

Yu, Zhiyi; IJzerman, Adriaan P.; Heitman, Laura H.

doi:10.1111/bph.12967

Cited by 33 publications

(48 citation statements)

References 53 publications

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“…Half-maximal inhibitory concentrations (ie, IC 50 values), apparent inhibitory binding constants (K i values), dissociation rate constants (k off ), and half-maximal effective concentrations (ie, EC 50 values) were calculated as previously described. 18 Values obtained from the radioligand-binding assays are from 3 different experiments each consisting of at least 2 independent samples. Data are expressed as mean±standard error of the mean (SEM) for the radioligand-binding assays or as mean±standard deviation (SD) for the optical voltage mapping experiments.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Liu

Veldhoven

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background— Ventricular arrhythmias as a result of unintentional blockade of the K v 11.1 (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 In past years, several highly prescribed drugs have been withdrawn for their ability to cause such proarrhythmia.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 K v 11.1 allosteric modulators. Methods and Results— Using [ 3 H]dofetilide-binding assays with membranes of human K v 11.1-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 K v 11.1 channel, with LUF7244 showing the strongest effect at 10 μmol/L. The K v 11.1 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 K v 11.1 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 K v 11.1 blockers via pharmacological combination therapy.

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Section: Discussionmentioning

confidence: 99%

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Liu

Veldhoven

et al. 2016

Circ: Arrhythmia and Electrophysiology

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“…Traditional low‐throughput techniques for measuring effects on these channels such as the manual patch clamp, although very sophisticated and accurate, have been complemented in recent years by reliable and more affordable high‐throughput technologies, which allow simultaneous automated screening of many compounds and ion channels. A recent alternative, although not yet formally approved as a replacement for the standard hERG blockade assay, is the use of [ 3 H]‐dofetilide displacement from K v 11.1 channels assessed as radioactive decay over time when the [ 3 H]‐dofetilide is displaced by higher affinity, non‐radioactive compounds competing for its same binding site (Diaz et al , 2004; Yu et al , 2015). Although this increases the throughput over classical assays, it falls short in capturing the functional and biophysical aspects of hERG blocks, in particular for those compounds that do not compete for the dofetilide binding site on K v 11.1 channels.…”

Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…In vitro K i estimates (Yu et al. ) were used as priors during model estimation and standard errors were used as variance of these priors (Langdon et al. ).…”

Section: Methodsmentioning

confidence: 99%

Application of a systems pharmacology model for translational prediction of hERG ‐mediated QT c prolongation

Gotta

Cools

et al. 2016

Pharmacol Res Perspect

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Drug‐induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG‐mediated QTc prolongation has been suggested. Also, in vivo between‐species and patient populations’ sensitivity to drug‐induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog–human differences in sensitivity to drug‐induced QTc prolongation (for dofetilide only). Scaling parameters for translational in vivo extrapolation of drug effects were derived based on the assumption of system‐specific myocardial ion channel densities and transduction of ion channel block: the operational efficacy (transduction of hERG block) in dogs was drug specific (1–19% hERG block corresponded to ≥10 msec Δ QTc). System‐specific maximal achievable Δ QTc was estimated to 28% from baseline in both dog and human, while %hERG block leading to half‐maximal effects was 58% lower in human, suggesting a higher contribution of hERG‐mediated potassium current to cardiac repolarization. These results suggest that differences in sensitivity to drug‐induced QTc prolongation may be well explained by drug‐ and system‐specific differences in operational efficacy (transduction of hERG block), consistent with experimental reports. The proposed scaling approach may thus assist the translational risk assessment of QTc prolongation in different species and patient populations, if mediated by the hERG channel.

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K_v11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical K_v11.1 (hERG) inhibitors

Cited by 33 publications

References 53 publications

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Application of a systems pharmacology model for translational prediction of hERG ‐mediated QT c prolongation

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Kv11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors

Cited by 33 publications

References 53 publications

Allosteric Modulation of K v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Allosteric Modulation of K v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Application of a systems pharmacology model for translational prediction of hERG ‐mediated QT c prolongation

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K_v11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical K_v11.1 (hERG) inhibitors

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias

Allosteric Modulation of K _v 11.1 (hERG) Channels Protects Against Drug-Induced Ventricular Arrhythmias