A "target class" screen to identify activators of two-pore domain potassium (K2P) channels

McCoull, David, Ococks, Emma, Large, Jonathan M, Tickle, David C, Mathie, Alistair, Jerman, Jeffrey and Wright, Paul D (2021) A "target class" screen to identify activators of two-pore domain potassium (K2P) channels. SLAS discovery : advancing life sciences R & D, 26 (3). pp. 428-438. ISSN 2472-5560

A target class.pdf - Published Version
Available under License Creative Commons Attribution Non-commercial No Derivatives.

Download (582kB) | Preview


Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a "target class" approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration-response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

Item Type: Article
Uncontrolled Keywords: ion channel, K2P, screening, potassium channel, assay
Subjects: Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
T Technology > TP Chemical technology
Divisions: Faculty of Health & Science > Department of Science & Technology
Depositing User: Alistair Mathie
Date Deposited: 01 Mar 2021 10:37
Last Modified: 01 Mar 2021 11:14
URI: https://oars.uos.ac.uk/id/eprint/1650

Actions (login required)

View Item View Item


Downloads per month over past year