Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)

Thomas, Dierk; Hammerling, Bettina C.; Wimmer, Anna Britt; Wu, Kezhong; Ficker, Eckhard; Kuryshev, Yuri A.; Scherer, Daniel; Kiehn, Johann; Katus, Hugo A.; Schoels, Wolfgang; Karle, Christoph A.

doi:10.1016/j.cardiores.2004.07.023

Cited by 47 publications

(23 citation statements)

References 28 publications

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“…The hERG-inhibitor effect of bisindolylmaleimide I has been previously described by Thomas et al (2004b) presenting results very congruent with ours. The EC 50 value obtained in HEK cells was 0.76 µM in our, while 1 µM in their experiments.…”

Section: Discussionsupporting

confidence: 92%

“…The EC 50 value obtained in HEK cells was 0.76 µM in our, while 1 µM in their experiments. 1 µM 11 bisindolylmaleimide I caused a 69.2 % inhibition in the native I Kr of guinea pig (Thomas et al 2004b) and a 69.4 % blockade of canine I Kr (present study). An interesting difference between the results of the two studies can be observed in the kinetic properties of I Kr blockade.…”

Section: Discussionsupporting

confidence: 61%

“…An interesting difference between the results of the two studies can be observed in the kinetic properties of I Kr blockade. We found a marked leftward shift of -12.2 mV in the voltage-dependence of I Kr activation in the presence of bisindolylmaleimide I, while only a small, statistically not significant change of -2.9 mV was seen by Thomas et al (2004b). The reason for this discrepancy is not clear at present, it might partly be caused by an improvement of voltage control due to reduction of hERG current amplitudes.…”

Section: Discussioncontrasting

confidence: 60%

“…Although bisindolylmaleimide I has been previously reported to block hERG current directly (Thomas et al 2004b), we are first to report a direct inhibition of hERG current and canine I Kr by another PKC inhibitor, chelerythrine.…”

Section: Discussionmentioning

confidence: 76%

“…These conditions, however, have never been controlled, except for an early study demonstrating that I Kr was directly blocked by bisindolylmaleimide I in guinea pig ventricular cells (Thomas et al 2004b). The aim of the present work was to study the effects of two frequently used PKC inhibitors, chelerythrine and bisindolylmaleimide I, on the rapid and slow components of the delayed rectifier K + current (I Kr and I Ks ) in ventricular cardiomyocytes of the dog, a species having action potential characteristics and properties of the underlying transmembrane ion currents most resembling the human (Szentandrássy et al 2005.…”

Section: Introductionmentioning

confidence: 99%

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Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents

Harmati

Papp

Szentandrássy

et al. 2010

Naunyn-Schmied Arch Pharmacol

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PKC inhibitors are useful tools for studying PKC-dependent regulation of ion channels.For this purpose high PKC specificity is a basic requirement excluding any direct interaction between the PKC inhibitor and the ion channel. In the present study the effects of two frequently applied PKC inhibitors, chelerythine and bisindolylmaleimide I, were studied on the rapid and slow components of the delayed rectifier K + current (

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 61%

Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents

Harmati

Papp

Szentandrássy

et al. 2010

Naunyn-Schmied Arch Pharmacol

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Catalytic and Stoichiometric Synthesis of Novel 3‐Aminocarbonyl‐, 3‐Alkoxycarbonyl‐, and 3‐Amino‐4‐indolylmaleimides

et al. 2008

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Novel nonsymmetrically substituted 4‐indolylmaleimides have been synthesized via palladium‐catalyzed alkoxy‐ and aminocarbonylation of 3‐bromo‐1‐methyl‐4‐(2‐methyl‐3‐indolyl)maleimide (1) with alcohols and amines in the presence of carbon monoxide. The resulting carboxamide derivatives represent a new class of potentially bioactive compounds. In addition, the direct amination reaction of 1 proceeded smoothly in the absence of catalyst and gave the desired 3‐amino‐4‐indolylmaleimides in good yields.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

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Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Polak¹,

Wiśniowska

Brandys³

2008

J of Applied Toxicology

100

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The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug-hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC(50)) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC(50) values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC(50) data available in accessible scientific literature to provide a high-quality data set for further studies.

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Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X)

Abstract: In summary, PKC-independent effects have to be carefully considered when using BIM I as PKC inhibitor in experimental models involving hERG channels and I(Kr) currents.

Cited by 47 publications

References 28 publications

Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents

Effects of the PKC inhibitors chelerythrine and bisindolylmaleimide I (GF 109203X) on delayed rectifier K+ currents

Catalytic and Stoichiometric Synthesis of Novel 3‐Aminocarbonyl‐, 3‐Alkoxycarbonyl‐, and 3‐Amino‐4‐indolylmaleimides

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

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