Acquired QT interval prolongation and HERG: implications for drug discovery and development.

Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I(Kr)), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.

[1]  Ward Oc.  A NEW FAMILIAL CARDIAC SYNDROME IN CHILDREN. , 1964 .

[2]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[3]  Charles Antzelevitch,et al.  Assessing predictors of drug-induced torsade de pointes. , 2003, Trends in pharmacological sciences.

[4]  J. Vandenbroucke,et al.  QT Interval Prolongation Predicts Cardiovascular Mortality in an Apparently Healthy Population , 1991, Circulation.

[5]  Hua-rong Lu,et al.  In vivo measurement of QT prolongation, dispersion and arrhythmogenesis: application to the preclinical cardiovascular safety pharmacology of a new chemical entity , 2002, Fundamental & clinical pharmacology.

[6]  Wataru Shimizu,et al.  Cellular mechanisms underlying the long QT syndrome. , 2002, Current opinion in cardiology.

[7]  Jun Zhou,et al.  Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. , 2002, The Journal of pharmacology and experimental therapeutics.

[8]  J. Miller,et al.  Low-level exercise testing after myocardial infarction: usefulness in enhancing clinical risk stratification. , 1985, Circulation.

[9]  Todd Wisialowski,et al.  Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. , 2004, European journal of pharmacology.

[10]  W. F. Hoffman,et al.  Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding. , 2004, Bioorganic & medicinal chemistry letters.

[11]  J. M. Di Diego,et al.  Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation , 2003, Circulation.

[12]  P. Davey.  Influence of posture and handgrip on the QT interval in left ventricular hypertrophy and in chronic heart failure. , 1999, Clinical science.

[13]  Robert Pearlstein,et al.  Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. , 2003, Journal of medicinal chemistry.

[14]  T. Garyantes,et al.  Development and Evaluation of High Throughput Functional Assay Methods for hERG Potassium Channel , 2001, Journal of biomolecular screening.

[15]  S. Lipsius,et al.  Effects of extracellular Mg2+ on T- and L-type Ca2+ currents in single atrial myocytes. , 1990, The American journal of physiology.

[16]  M. Arsenian.  Magnesium and cardiovascular disease. , 1993, Progress in cardiovascular diseases.

[17]  Jules C Hancox,et al.  Inhibitory actions of the selective serotonin re‐uptake inhibitor citalopram on HERG and ventricular L‐type calcium currents , 2002, FEBS letters.

[18]  Marc A. Vos,et al.  Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts , 2003, Journal of Pharmacology and Experimental Therapeutics.

[19]  Paul B Bennett,et al.  Trends in ion channel drug discovery: advances in screening technologies. , 2003, Trends in biotechnology.

[20]  W. Crumb,et al.  Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. , 2002, The Journal of pharmacology and experimental therapeutics.

[21]  J. Weiss,et al.  Diurnal pattern of QTc interval: how long is prolonged? Possible relation to circadian triggers of cardiovascular events. , 1996, Journal of the American College of Cardiology.

[22]  Y. Jan,et al.  Molecular studies of voltage-gated potassium channels. , 1990, Cold Spring Harbor symposia on quantitative biology.

[23]  G. Duker,et al.  Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic , 2001, Circulation.

[24]  Maurizio Recanatini,et al.  Safety of Non-Antiarrhythmic Drugs that Prolong the QT Interval or Induce Torsade de Pointes , 2002, Drug safety.

[25]  E. Grishin,et al.  A radiolabeled peptide ligand of the hERG channel, [125I]-BeKm-1 , 2003, Pflügers Archiv.

[26]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[27]  T J Campbell,et al.  HERG K+ channels: friend and foe. , 2001, Trends in pharmacological sciences.

[28]  A. Moss,et al.  The Long QT Syndrome: Prospective Longitudinal Study of 328 Families , 1991, Circulation.

[29]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[30]  Cavero,et al.  QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development. , 1999, Pharmaceutical science & technology today.

[31]  K. Finlayson,et al.  A High-Throughput Binding Assay for HERG , 2004 .

[32]  R. Gilmour.  A novel approach to identifying antiarrhythmic drug targets. , 2003, Drug discovery today.

[33]  A J Camm,et al.  Evaluation of Drug-Induced QT Interval Prolongation , 2001, Drug safety.

[34]  J. Mitcheson,et al.  Molecular determinants of high-affinity drug binding to HERG channels. , 2003, Current opinion in drug discovery & development.

[35]  R. MacKinnon.  Determination of the subunit stoichiometry of a voltage-activated potassium channel , 1991, Nature.

[36]  M. Sanguinetti,et al.  Role of delayed rectifier potassium channels in cardiac repolarization and arrhythmias , 1997 .

[37]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[38]  S. O’Donoghue,et al.  Levofloxacin Induced Polymorphic Ventricular Tachycardia with Normal QT Interval , 2001, Pacing and clinical electrophysiology : PACE.

[39]  A. S. Davis.  The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods , 1998, Human & experimental toxicology.

[40]  Andreas Ebneth,et al.  HTS techniques to investigate the potential effects of compounds on cardiac ion channels at early-stages of drug discovery. , 2003, Current opinion in drug discovery & development.

[41]  C. Romano.  CONGENITAL CARDIAC ARRHYTHMIA. , 1965, Lancet.

[42]  J. Warmke,et al.  A family of potassium channel genes related to eag in Drosophila and mammals. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[43]  B. Halmos,et al.  Interpopulation effect of ACE I/D polymorphism on serum concentration of ACE in diagnosis of sarcoidosis , 1997, The Lancet.

[44]  O. Pongs,et al.  Screening lead compounds for QT interval prolongation. , 2001, Drug discovery today.

[45]  Y. Jan,et al.  Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. , 1987, Science.

[46]  Hua-rong Lu,et al.  Detection of Proarrhythmia in the Female Rabbit Heart: , 2003, Journal of cardiovascular electrophysiology.

[47]  M. Jiang,et al.  Mapping the Binding Site of a Humanether-a-go-go-related Gene-specific Peptide Toxin (ErgTx) to the Channel's Outer Vestibule* , 2002, The Journal of Biological Chemistry.

[48]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[49]  Steven L. Cohen,et al.  DEPARTMENT OF PHYSIOLOGY: 2016/2017 LT/LE ORGANIZATION CHART , 2016 .

[50]  G. Breithardt,et al.  Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients , 2004, Journal of Molecular Medicine.

[51]  Gisbert Schneider,et al.  A Virtual Screening Method for Prediction of the hERG Potassium Channel Liability of Compound Libraries , 2002, Chembiochem : a European journal of chemical biology.

[52]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[53]  J. Hancox,et al.  Preferential closed channel blockade of HERG potassium currents by chemically synthesised BeKm‐1 scorpion toxin , 2003, FEBS letters.

[54]  A. Cavalli,et al.  Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. , 2002, Journal of medicinal chemistry.

[55]  J. Henry.  Epidemiology and Relative Toxicity of Antidepressant Drugs in Overdose , 1997, Drug safety.

[56]  H. DeBlock,et al.  Effect of short- and long-duration spaceflight on QTc intervals in healthy astronauts. , 2003, The American journal of cardiology.

[57]  A. Mangoni,et al.  Impact of age on QT interval and QT dispersion in healthy subjects: a regression analysis. , 2003, Age and ageing.

[58]  P. Hoffmann,et al.  Blinded Test in Isolated Female Rabbit Heart Reliably Identifies Action Potential Duration Prolongation and Proarrhythmic Drugs: Importance of Triangulation, Reverse Use Dependence, and Instability , 2003, Journal of cardiovascular pharmacology.

[59]  Calum A. MacRae,et al.  Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish , 2003, Circulation.

[60]  Rita R. Patel,et al.  A High-Throughput HERG Potassium Channel Function Assay: An Old Assay with a New Look , 2002, Drug development and industrial pharmacy.

[61]  J. Valentin,et al.  The application of in vitro methods to safety pharmacology , 2002, Fundamental & clinical pharmacology.

[62]  P. Puddu,et al.  Screening for drug-induced (acquired) long QT syndrome: is it time to apply new methods? , 2001, European heart journal.

[63]  M. Sanguinetti,et al.  Mutations in the hminK gene cause long QT syndrome and suppress lKs function , 1997, Nature Genetics.

[64]  P. C. Viswanathan,et al.  Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes , 2002, Circulation.

[65]  A. Camm,et al.  Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. , 2003, Cardiovascular research.

[66]  S. Heinemann,et al.  Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. , 1996, The Journal of physiology.

[67]  B. Darpö,et al.  Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes , 2001 .

[68]  F. Ponti,et al.  QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience , 2000, European Journal of Clinical Pharmacology.

[69]  D. Nutt,et al.  Psychotropic Drugs, Cardiac Arrhythmia, and Sudden Death , 2003, Journal of clinical psychopharmacology.

[70]  Harry J. Witchel,et al.  Time course and voltage dependence of expressed HERG current compared with native ”rapid” delayed rectifier K current during the cardiac ventricular action potential , 1998, Pflügers Archiv.

[71]  K. Olejniczak,et al.  ICH Topic: The draft ICH S7B step 2: Note for guidance on safety pharmacology studies for human pharmaceuticals , 2002, Fundamental & clinical pharmacology.

[72]  D. Mcnamara,et al.  Heritable Q‐T Prolongation Without Deafness , 1970, Circulation.

[73]  J. Hancox,et al.  Antiarrhythmics—from cell to clinic: past, present, and future , 2000, Heart.

[74]  C Antzelevitch,et al.  The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. , 2000, European heart journal.

[75]  Paul B Bennett,et al.  High throughput ion-channel pharmacology: planar-array-based voltage clamp. , 2003, Assay and drug development technologies.

[76]  M. Lazdunski,et al.  APETx1, a new toxin from the sea anemone Anthopleura elegantissima, blocks voltage-gated human ether-a-go-go-related gene potassium channels. , 2003, Molecular pharmacology.

[77]  Jun Chen,et al.  A structural basis for drug-induced long QT syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[78]  C. January,et al.  [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. , 2001, European journal of pharmacology.

[79]  M. Leppert,et al.  The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. , 1992, The New England journal of medicine.

[80]  Clay W Scott,et al.  A medium-throughput functional assay of KCNQ2 potassium channels using rubidium efflux and atomic absorption spectrometry. , 2003, Analytical biochemistry.

[81]  F Dessertenne,et al.  [Ventricular tachycardia with 2 variable opposing foci]. , 1966, Archives des maladies du coeur et des vaisseaux.

[82]  A. J. Pennington,et al.  [3H]dofetilide binding in SHSY5Y and HEK293 cells expressing a HERG-like K+ channel? , 2001, European journal of pharmacology.

[83]  D. Roden,et al.  Drug Block of I Kr : Model Systems and Relevance to Human Arrhythmias , 2001, Journal of cardiovascular pharmacology.

[84]  R. Lukas,et al.  Some methods for studies of nicotinic acetylcholine receptor pharmacology , 2001 .

[85]  A. Jervell,et al.  Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death , 1957 .

[86]  R. Young,et al.  Optimization of a tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors: structure-activity relationship related to PDE4 inhibition and human ether-a-go-go related gene potassium channel binding affinity. , 2003, Journal of medicinal chemistry.

[87]  G. Keserü.  Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. , 2003, Bioorganic & medicinal chemistry letters.

[88]  Jules C Hancox,et al.  Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes. , 2002, Journal of pharmacological and toxicological methods.

[89]  G. Gintant,et al.  Tissue and species distribution of mRNA for the IKr-like K+ channel, erg. , 1997, Circulation research.

[90]  G. Terstappen,et al.  Functional analysis of native and recombinant ion channels using a high-capacity nonradioactive rubidium efflux assay. , 1999, Analytical biochemistry.

[91]  M. Gralinski.  The Dog's Role in the Preclinical Assessment of QT Interval Prolongation , 2003, Toxicologic pathology.

[92]  M. Chung,et al.  Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. , 2004, Cardiovascular research.

[93]  Youxing Jiang,et al.  The open pore conformation of potassium channels , 2002, Nature.

[94]  Soo Sen Lee,et al.  Flux assays in high throughput screening of ion channels in drug discovery. , 2003, Assay and drug development technologies.

[95]  A. Moss,et al.  The long QT syndrome: a prospective international study. , 1985, Circulation.

[96]  Hao Wang,et al.  Functional and pharmacological properties of canine ERG potassium channels. , 2003, American journal of physiology. Heart and circulatory physiology.

[97]  J. Barlow,et al.  CONGENITAL CARDIAC ARRHYTHMIA , 1964 .

[98]  Rory Curtis,et al.  A Novel Membrane Potential-Sensitive Fluorescent Dye Improves Cell-Based Assays for Ion Channels , 2002, Journal of biomolecular screening.

[99]  B. Fermini,et al.  The impact of drug-induced QT interval prolongation on drug discovery and development , 2003, Nature Reviews Drug Discovery.

[100]  Derek Leishman,et al.  Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. , 2002, Current opinion in drug discovery & development.

[101]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[102]  C. January,et al.  Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. , 1998, Biophysical journal.

[103]  Joel Morganroth,et al.  A definitive or thorough phase 1 QT ECG trial as a requirement for drug safety assessment. , 2004, Journal of electrocardiology.

[104]  G. Breithardt,et al.  Experimental models of torsade de pointes. , 1998, Cardiovascular research.

[105]  B. Chait,et al.  The structure of the potassium channel: molecular basis of K+ conduction and selectivity. , 1998, Science.

[106]  R. Shah,et al.  The significance of QT interval in drug development. , 2002, British journal of clinical pharmacology.