Disease relevance of CUZD1

• The most common problem is acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K(+) channels, delay cardiac repolarization and increase the risk of torsades de pointes arrhythmia (TdP) [1].
• Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome [2].
• In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/IKr or any other cardiac potassium current at therapeutic concentrations [3].
• METHODS: The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease) [4].
• The protein product of the human ether-a-go-go gene (hERG) is a potassium channel that when inhibited by some drugs may lead to cardiac arrhythmia [5].

High impact information on CUZD1

• We found that 1a and 1b N-terminal fragments bind in a direct and dose-dependent manner. hERG1 hetero-oligomerization occurs in the endoplasmic reticulum where co-expression of N-terminal fragments with hERG1 subunits disrupted oligomerization and core glycosylation [6].
• Alternate transcripts of the human ether-à-go-go-related gene (hERG1) encode two subunits, hERG 1a and 1b, which form potassium channels regulating cardiac repolarization, neuronal firing frequency, and neoplastic cell growth [6].
• These are then evaluated in the light of pharmacokinetics prediction (e.g. Caco-2 permeability, cytochrome P450 inhibition and hERG binding) [7].
• Comprehensive evaluation of quantitative ERG1 expression with clinicopathological features also suggested that ERG1 expression level in prostate tumor cells relative to benign epithelial cells is indicator of disease-free survival after radical prostatectomy [2].
• In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC50, 11.8 microM) and inhibits hERG maturation on Western blots (IC50, 62 microM) [3].

Chemical compound and disease context of CUZD1

• Dietary intake of caffeine is unlikely to cause long QT syndrome because plasma concentrations do not reach sufficiently high levels to significantly inhibit hERG currents [8].
• Taken together, our data imply that chronic administration of pentamidine at clinically relevant exposure reduces the membrane expression of the hERG channel, which may most likely be the major mechanism of QT prolongation and torsade de pointes reported in man [9].
• Trazodone has been associated with prolonged QT-interval and increased risk of polymorphous ventricular tachycardias clinically and has demonstrated in vitro inhibition of hERG (human ether-á-go-go-related gene) channel current [10].
• Taken together, these data provide evidence that dopamine receptor agonists developed for the treatment of Parkinson's disease differentially influence hERG K(+) channel function and cardiac action potential duration [11].
• Four dopamine receptor agonists used for the treatment of Parkinson's disease (apomorphine, pergolide, ropinirole and sumanirole) were evaluated for the ability to block human ether-a-go-go related gene (hERG) K(+) channels and to modify the duration of canine Purkinje fiber action potentials [11].

Biological context of CUZD1

• Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625) [12].
• We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions [12].
• Unexpectedly, upon co-expression of p.Pro872fs and WT channels, the repolarising power (the proportion of hERG current contributing to the action potential as the percentage of the total current available) was substantially higher during action potential clamp experiments as compared to WT channels alone [13].
• These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles [14].
• A 'global' model of hERG K(+) channel was built to satisfy three basic criteria for QSAR models in drug discovery: (1) assessment of the applicability domain, (2) assuring that model decisions can be interpreted by medicinal chemists and (3) assessment of model performance after the model was built [15].

Anatomical context of CUZD1

• Here, we characterize the effects of this compound on cloned hERG channels heterologously expressed in Xenopus laevis oocytes [16].
• In a stable HEK-293 cell line, we observed a concentration-dependent inhibition of the hERG current with an IC50 of 252 microM [9].
• The human ether-a-go-go-related gene (hERG) potassium channel is expressed in a variety of cell types, including neurons, tumor cells, and cardiac myocytes [8].
• The biophysical and pharmacological properties of the Cs+-carried human ether-a-go-go-related gene (hERG) current were very similar to those of the Cs+-carried I(Kr) in ventricular myocytes [17].
• In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity [18].

Associations of CUZD1 with chemical compounds

• CONCLUSIONS: The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide [4].
• In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block [12].
• Both L-arginine (10 mM) and NOC-18 (0.3 mM) counteracted the stimulatory effect on hERG1 outward currents induced by the radical oxygen species-generating system FeSO(4) (25 microM)/ascorbic acid (50 microM; Fe/Asc) [19].
• Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine (E-4031) and dofetilide) [20].
• Extracellular Cd(2+) modulates hERG channel activation by binding to a coordination site formed, at least in part, by three Asp residues [21].

Analytical, diagnostic and therapeutic context of CUZD1

• The molecular determinants of hERG channel blockade have been defined using a site-directed mutagenesis approach [1].
• Circular dichroism and NMR analysis of a synthetic hERG S5-P linker peptide suggested that this linker is quite dynamic: its central region (positions 583-593) can be unstructured or helical, depending on whether it is immersed in an aqueous phase or in contact with a hydrophobic environment [22].
• The effects of MTX on hERG channels were investigated using the patch-clamp technique [23].
• This includes (1) testing for blockade of I(Kr) or hERG-mediated potassium current in heterologous cell systems, (2) measurement of effects on the myocardial action potential in vitro; and (3) assessment of effects on the ECG in a well-conducted in vivo study [24].
• Cells prepared from normal cultures and following cryopreservation were compared with regard to time course of Rb+ efflux response at different concentrations of KCl, overall cell morphology, signal-to noise assay window, assay robustness, and 50% inhibitory concentration (IC50) of the hERG blocker dofetilide [25].

References