Characterization of A-935142, a hERG enhancer, in the presence and absence of standard hERG blockers

Liu, Xiaoqin; Limberis, James T.; Su, Zhi; Houseman, Kathryn; Diaz, Gilbert; Gintant, Gary A.; Cox, Bryan F.; Martin, Ruth L.

doi:10.1016/j.lfs.2012.02.017

Cited by 10 publications

(11 citation statements)

References 19 publications

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“…Several hERG activators were especially known to occupy these putative binding sites in hERG. For instance, compound A‐935142 is a known hERG activator that binds to these putative sites of the channel. The existence of several binding sites for diverse hERG modulators indicates the possibility of an allosteric mechanism, which is yet to be understood.…”

Section: Herg Channel: Structural Topologymentioning

confidence: 99%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

110

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Drug-induced blockade of human ether-a-go-go-related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off-target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure-based models of hERG have been developed as a low-cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off-target interactions with hERG.

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Section: Herg Channel: Structural Topologymentioning

confidence: 99%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

110

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“…A-935142 does not compete with 3 H-dofetilide binding, nor does it exhibit functional competition with other hERG1 blockers (terfenadine or sotalol) [35]. Scanning mutagenesis of hERG1 and functional characterization of heterologously expressed mutant channels also suggests that the binding sites for hERG1 blockers and agonists differ.…”

Section: Molecular Determinants Of Agonist Activitymentioning

confidence: 99%

HERG1 channel agonists and cardiac arrhythmia

Sanguinetti¹

2014

Current Opinion in Pharmacology

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Type 1 human ether-a-go-go-related gene (hERG1) potassium channels are a key determinant of normal repolarization of cardiac action potentials. Loss of function mutations in hERG1 channels cause inherited long QT syndrome and increased risk of cardiac arrhythmia and sudden death. Many common medications that block hERG1 channels as an unintended side effect also increase arrhythmic risk. Routine preclinical screening for hERG1 block led to the discovery of agonists that shorten action potential duration and QT interval. Agonists have the potential to be used as pharmacotherapy for long QT syndrome, but can also be proarrhythmic. Recent studies have elucidated multiple mechanisms of action for these compounds and the structural basis for their binding to the pore domain of the hERG1 channel.

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“…(3) KB130015 regulates the hERG channel by increasing activation [18] . (4) A-935142 and mallotoxin both regulate the hERG channel by changing multiple kinetics [20,83] . (5) Matrine and oxymatrine influence the hERG channel by up-regulating transcription instead of changing kinetics [22,85] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…Importantly, many activators are capable of shortening prolonged APD and the QT interval. For example, RPR260243 is able to reverse dofentilide-induced APD prolongation by slowing down hERG deactivation to increase I [kr] [ [18][19][20] . In addition, PD118057 can reduce hERG inactivation, shift up inactivation potential and prevent dofetilide-caused QT interval prolongation [18,84] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…In addition, the hERG channel blocker E-4031 is able to remove the traffickingdeficient G601S-hERG channel from a microtubule-dependent quality control compartment and increase export from the ER [17] . Meanwhile, the hERG channel activator RPR260243 can slow down hERG channel deactivation, increase I [Kr] and reverse dofentilide-induced action potential duration (APD) and prolongation [18][19][20] . Rescue strategies are also being developed from the biological regulating factors of the hERG channel.…”

Section: Introductionmentioning

confidence: 99%

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Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Zhang

Yang

2014

Acta Pharmacol Sin

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The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.

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Characterization of A-935142, a hERG enhancer, in the presence and absence of standard hERG blockers

Cited by 10 publications

References 19 publications

Development of Safe Drugs: The hERG Challenge

Development of Safe Drugs: The hERG Challenge

HERG1 channel agonists and cardiac arrhythmia

Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

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