Ion channel drug discovery with leading-edge facilities and a strategic approach!
Drug discovery ability to overcome challenges

Published on October 2, 2020
# ion channel-targeted drug # HTS # SyncroPatch 384PE

To provide ideal hit compounds to clients who want to create ion channel-targeted drugs, Axcelead Drug Discovery Partners (hereinafter referred to as Axcelead DDP) is enhancing a new screening service, for example, constructing assay systems for high-throughput screening (HTS) with the use of automated patch clamp system (SyncroPatch 384PE). This time, we interviewed three specialists in ion channel drug discovery!

1.Outspread potential of ion channel drug discovery

Thank you for the opportunity today! Firstly, can you tell me what type of ion channel-targeted drugs exist?

Hibino: About 20% of all proteins targeted for drug discovery are considered to be ion channels. Major disease areas include the cardiovascular system, the central nervous system, and pain. In recent years,
drugs targeting ion channels have been developed for the immune system and cancer, too. Ion channels are involved in a variety of diseases, which makes them an attractive target for drug discovery.

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I see. What specifically makes the ion channel-targeted drug discovery so difficult?

Seki: Ion channels are widely present in the organs that are fundamental for life activity, such as the heart and brain, so that the drugs targeting ion channels are likely to cause critical adverse reactions, including cardiac and neurological toxicities. How to avoid such adverse reactions is the key to the development of ion channel-targeted drugs.
What do you think about the future possibility of ion channels as a target for drug discovery?

Hirano: Thanks to biology advancement, the identification and validation of molecules causing diseases are making progress. Also, analyses of the localization and molecular complexity of ion channels are advancing, and functional analysis tools and assay systems are evolving from day to day. So, I believe brand-new drug discovery is possible even for the same targets as before.

2.Proposing an optimal screening strategy that matches the ideal compound image

Tell me about screening strategies.

Hibino: Usually, screening consists of three steps: HTS (primary screening), that selects a few thousand from hundreds of thousands of compounds; 2nd screening, that confirms and selects positive compounds; and profiling, that selects or prioritizes hit compounds. Screening strategies can make a large difference in the resulting hit compounds and their mode of action (MOA) as well as in development speed and cost.

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What kind of assay methods can be used for ion channel targets?

Hirano: The gold-standard method is an electrophysiological approach, which directly examines ion channel functions. There are two methods to this approach: one is a manual patch clamp method, in which the data are manually obtained from a single cell, and the other is an automated patch clamp method, in which the manual patch clamp method is automatized to enable simultaneous data collection from multiple cells. Besides these, a method for measuring ion concentration or membrane potential change using fluorescent dyes, and a method based on Fluorescence/Bioluminescence Resonance Energy Transfer (FRET/BRET) are used.
Many methods are available. How do you choose which method to use?

Seki: In the past, the electrophysiological approach was difficult to use for evaluating hundreds of thousands of compounds due to its processing capacity. Therefore, the mainstream method was to conduct primary screening using certain indexes, such as intracellular ion concentration, membrane potential, and compound bond, and then perform the electrophysiological approach or cellular function assessment. But, recently, as technology has been advancing, high-processing capacity automated patch clamping has become available, so now the electrophysiological approach can be used for primary screening. Axcelead DDP has gained a lot of experience in HTS with various evaluation methods. We are proposing the best screening strategy, and will choose the most suitable evaluation methods depending on the client’s needs.


To choose the best approach, experience in ion channel drug discovery can be important. Have you all been working on ion channel drug discovery research?

Hirano: I have been conducting research focusing on ion channel molecular complexity, and research on in vivo functional expression of receptors and transporters. I would like to support clients in drug discovery with my experience in the multidimensional evaluation of ion channel functions with the use of electrophysiology, gene engineering, biochemistry, and imaging technology.
Seki: I have been working on ion channel drug discovery for a variety of target diseases, ranging from screening to candidate compound creation, for about a decade. In my previous job, my main task was the manual patch clamp approach, and I experienced many joint research projects with large pharmaceutical companies both domestically and internationally. With my accumulated experience, I would like to propose the best screening strategy and protocol, considering which points need attention for proceeding to drug discovery research, to academic sectors and entrepreneurial ventures who own intriguing evaluation methods or compounds.
Hibino: I worked in the pharmacology division of a pharmaceutical company for a decade and engaged in various research processes, ranging from the start of preclinical research to the bridge to clinical development. Starting from the construction of evaluation methods for determining the target disease of developed compounds, then translational research with an eye to clinical phases, and eventually screening as the first step in drug discovery. By using all of my experience, I would like to propose a proactive screening strategy.
You all are working in the same area but have different backgrounds.
Gathering all of your strengths makes Axcelead DDP’s support system very encouraging!