What is hERG toxicity?
Background: hERG K(+) channels have been recognized as a primary antitarget in safety pharmacology. Their blockade, caused by several drugs with different therapeutic indications, may lead to QT prolongation and, eventually, to potentially fatal arrhythmia, namely torsade de pointes.
What does hERG stand for?
The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia.
What is hERG IC50?
The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax ) is used during drug development to screen out chemical entities likely to cause TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer.
What is hERG liability?
Introduction. The inhibition of the human ether-a-go-go (hERG) ion channel may cause QT interval prolongation, which eventually can result in torsades de pointes (TdP) [1] and even death. Hence cardiotoxicity caused by the inhibition of hERG is a major liability within the drug development process.
How does hERG channel work?
hERG forms the major portion of one of the ion channel proteins (the ‘rapid’ delayed rectifier current (IKr)) that conducts potassium (K+) ions out of the muscle cells of the heart (cardiac myocytes), and this current is critical in correctly timing the return to the resting state (repolarization) of the cell membrane …
How is IC50 value calculated?
The values of y are in the range of 0-1. The simplest estimate of IC50 is to plot x-y and fit the data with a straight line (linear regression). IC50 value is then estimated using the fitted line, i.e., Y = a * X + b,IC50 = (0.5 – b)/a.
What is a good IC50 for a drug?
Generally, less than 10 micromolar concentration of a drug in plasma is accepted because higher than 10 uM of a drug inhibit necessary enzymes. The most of the drugs on the market have less than 10 micromolar therapeutic plasma concentrations.
How can I reduce my hERG activity?
Introduction of an aliphatic oxygen near to an amine can significantly reduce HERG binding, as can be seen below this can be ascribed to a reduction on the pKa of the basic nitrogen, but also the hydroxyl serves to reduce the overall lipophilicity.
Where are hERG channels found?
The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11. 1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines.
What happens when potassium channels are blocked?
Activation leads to an increase in conductance and the termination of action potentials, hyperpolarization, and a reduction in excitability. Conversely, a block of the channels leads to depolarization, prolongation of action potentials, repetitive firing, and increases in transmitter release and endocrine activity.
How is GI50 calculated?
The NCI renamed the IC50 value, the concentration that causes 50% growth inhibition, the GI50 value to emphasize the correction for the cell count at time zero; thus, GI50 is the concentration of test drug where 100 × (T – T0)/(C – T0) = 50 (3, 9).
Is a low or high IC50 good?
The IC50 value is correlated with drug potency, i.e. the amount of drug necessary to produce the effect—the lower the IC50 value the more potent the drug [33]. The relationship between drug potency, drug efficacy and the IC50 curve shape is shown in Fig.
Are there any side effects of hERG in humans?
The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years. In order to prevent the cardiac side effects, a great number of in silico, in vitro and in vivo assays have been performed.
Why are hERG toxicity assessments useful for drug design?
hERG toxicity assessment: Useful guidelines for drug design All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel.
Why do so many drugs fail the hERG test?
Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years.