The ion age

The ion age

Ion channels are protein structures embedded in the cell membrane of most cells in the body and are fundamentally important in membrane electrogenesis and cellular signaling. Ion channels are typically selective for different ions and have been used for a general classification into sodium, potassium, calcium and nonselective cation channels. The gating of these channels is by voltage and ligand binding. In view of their importance in the normal functioning of most cells, altered function can lead to pathophysiological states; channelopathies. Hence, ion channels are of great interest to the pharmaceutical industry since they represent important therapeutic targets.

Ion channel modulators are already a successful drug class including blockbusters such as the anti-hypertensive Norvasc (>US$4 billionn in the US). Other examples include anxiety treatments (Paxil) and insomnia treatments (Ambien). Drugs that modulate ion channels have also been investigated in therapeutic areas such as pain, cardiac arrhythmia, local anaesthesia, stroke, Parkinson’s, obesity, depression, allergy and cancer.

When compared to GPCR’s and kinases, ion channels are under exploited as drug targets by the pharmaceutical industry. It is well accepted by the pharmaceutical industry that one reason for this under exploitation is that ion channels are technically complex targets for which existing technology is resource intensive and inefficient. As such, they are not easily incorporated into the pharmaceutical industry’s drug discovery pipelines. In contrast to technologies for GPCR and enzyme targets, screening technologies for measuring the effect of compounds on functional ion channels have several orders of magnitude lower throughput. This makes screening chemical libraries for new lead compounds and optimising those leads for potency, selectivity and safety extremely difficult. As a result, pharmaceutical companies have historically focussed on deorphanised GPCR’s and kinases as drug targets.

However, over the last few years, there has been a drive towards the development of new technologies to enable higher throughput ion channel screening offering true voltage clamp. This has removed the bottlenecks that have previously resulted in the under exploitation of this target class. In addition to ion channels representing important therapeutic targets for drugs, interactions with other ion channels can lead to toxic effects e.g. blockade of hERG channels, causing drug-induced LQT syndrome that can lead to life threatening cardiac arrhythmias.

New higher throughput screening technologies have now become available from companies such as Molecular Devices Corporation, Sophion, Flyion, Cellectricon, Cytocentrics and Nanion.

Upstate has established its self as a supplier of unique reagents focused on providing the research tools that companies will need to use with these emerging technologies. Currently, it is the leading provider of stable recombinant ion channel cell lines (PrecisION) to the Pharmaceutical industry and to the biotechnology companies worldwide. These ion channel cell lines are functionally validated by both conventional patch clamp electrophysiology and by IonWorks HT and are available off-the-shelf. Upstate also offers, IonChannelProfiler, a contract ion channel screening service of compounds for its clients.

Development of ion channel expressing cell lines is highly technical, difficult and extremely time consuming. The products and services offered by Cytomyx are aimed at speeding up the customers ability to i) develop in-house screening assays against their primary ion channel targets, ii) develop relevant panels of assays to use in selectivity screening and iii) compound screening for cardiac side effects associated with hERG and other cardiac ion channels.

Selectivity screening is a well established concept in drug discovery with CRO’s like MDS, Cerep, Euroscreen and Novascreen offering broad panels of targets including GPCRs and kinases, on a simple fee structure. However, few of these companies offer panels of ion channel targets assessed by electrophysiology such as IonChannelProfiler does where compounds can be screened within gene families and across gene families for assessing selectivity, potency and efficacy.

Global regulatory guidelines (e.g. the FDA) require that all drug candidates are tested for the potential to cause long QT syndrome and an accepted method for this testing includes screening against the hERG ion channel.

However, many ion channels play a key role in the cardiac action potential and drugs that have had an effect on the heart is mainly to the hERG channel. Some drugs have been subsequently withdrawn from the market and great cost to the companies involved, due to QT prolongation that can lead to the potentially fatal tachyarrhythmia, Torsade de Points (TdP) (e.g. the anti-histamine, Seldane). However, some drugs that potently block hERG don’t prolong the QT interval and don’t cause TdP [e.g. Verapamil (Hypertension, Angina)]. Thus, there is no simple link between the block of hERG, the prolongation of the QT interval and the subsequent development of TdP. This is most likely due the blocking of more than one ion channel in the heart so that certain drugs will either have an increased or decreased pro-arrhythmic risk regardless of hERG channel block.

Upstate has therefore developed a panel of key cardiac ion channels (Cav1.2, Nav1.5, Kv1.5, KCNQ1/minK, Kv4.3/KchIP1) such that drug companies can, through IonChannelProfiler, screen their compounds against a range of these ion channels in addition to hERG which will help better assess any potential cardiac risk. By screening early in the drug discovery process (during hit-to-lead) and during SAR, companies can avoid costly withdrawal of drugs at a much later stage. In this way, Upstate can help drug companies not only to aid the development of cardiac drugs e.g. anti-arrhythmics, but also in the assessment of cardiac risk for all development compounds across all therapeutic areas