Key result
Thallium flux assay screening identifies novel K2P channel activators from FDA-approved compounds.
Why the study?
There is a lack of selective pharmacological tools for K2P channels despite their key role in regulating membrane potential and involvement in human pathophysiologies such as pain and migraine.
A target class screening approach using a thallium flux assay successfully identified novel small-molecule activators of K2P channels, providing new pharmacological tools for potential therapeutic intervention.
Expands K2P pharmacological tools; leaves open therapeutic relevance in cardiovascular disease pending validation.
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.
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McCoull et al. (2020) studied this question. FDA-approved compounds and LifeArc Index Set was evaluated on K2P channel activation. A target class screening approach using a thallium flux assay successfully identified novel small-molecule activators of multiple K2P channel subclasses from a library of FDA-approved compounds.
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