Academic Journal
A "Target Class" Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels.
| Τίτλος: | A "Target Class" Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels. |
|---|---|
| Συγγραφείς: | McCoull D; LifeArc, Stevenage, UK., Ococks E; LifeArc, Stevenage, UK., Large JM; LifeArc, Stevenage, UK., Tickle DC; LifeArc, Stevenage, UK., Mathie A; Medway School of Pharmacy, University of Kent, Chatham Maritime, Kent, UK., Jerman J; LifeArc, Stevenage, UK., Wright PD; LifeArc, Stevenage, UK. |
| Πηγή: | SLAS discovery : advancing life sciences R & D [SLAS Discov] 2021 Mar; Vol. 26 (3), pp. 428-438. Date of Electronic Publication: 2020 Dec 29. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: SAGE Publications Country of Publication: United States NLM ID: 101697563 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2472-5560 (Electronic) Linking ISSN: 24725552 NLM ISO Abbreviation: SLAS Discov Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Thousand Oaks, CA : SAGE Publications, [2017]- |
| Ιατρικοί όροι (MeSH): | High-Throughput Screening Assays*, Potassium Channels, Tandem Pore Domain/*genetics , Small Molecule Libraries/*pharmacology, Baculoviridae/genetics ; Baculoviridae/metabolism ; Drug Discovery/methods ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Genetic Vectors/chemistry ; Genetic Vectors/metabolism ; Potassium/metabolism ; Potassium Channels, Tandem Pore Domain/agonists ; Potassium Channels, Tandem Pore Domain/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Thallium/metabolism ; Cell Line, Tumor ; Cloning, Molecular ; Gene Expression ; Humans ; Ion Transport |
| Περίληψη: | 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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| Contributed Indexing: | Keywords: K2P; assay; ion channel; potassium channel; screening |
| Substance Nomenclature: | 0 (KCNK1 protein, human) 0 (KCNK10 protein, human) 0 (KCNK13 protein, human) 0 (KCNK5 protein, human) 0 (KCNK9 protein, human) 0 (Potassium Channels, Tandem Pore Domain) 0 (Recombinant Proteins) 0 (Small Molecule Libraries) AD84R52XLF (Thallium) RWP5GA015D (Potassium) |
| Entry Date(s): | Date Created: 20201230 Date Completed: 20220228 Latest Revision: 20220830 |
| Update Code: | 20260515 |
| PubMed Central ID: | PMC7900820 |
| DOI: | 10.1177/2472555220976126 |
| PMID: | 33375888 |
| Βάση Δεδομένων: | MEDLINE |
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