ArticleAnnals of neurology2025
Identification of New KCNT1-Epilepsy Drugs by In Silico, Cell, and Drosophila Modeling.
Article in Annals of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveHyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and, in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. There are currently no effective treatments for KCNT1 epilepsies, but suppressing overactive channels poses a potential strategy.
methodsUsing the KCNT1 channel structure we in silico screened a library of known drugs for those predicted to block the channel pore to inhibit channel activity. Cellular KCNT1 channel inhibition was analyzed using electrophysiology and Drosophila bang-sensitive assays were used to analyze seizure suppression. Brain penetration of one drug was analyzed using liquid chromatography-mass spectrometry in a mouse.
resultsEight known drugs were investigated in vitro for their effects on patient-specific mutant KCNT1 channels, with 4 drugs showing significant reduction of K
interpretationThis study identified a known drug, antrafenine, that reduces KCNT1 channel activity, reduces seizure activity in Drosophila, and crosses the blood-brain barrier in the mouse, suggesting its potential applicability as a new treatment for KCNT1 epilepsy. The sequential in silico, in vitro, and in vivo mechanism-based drug selection strategy used here may have broader application for other human disorders where a disease mechanism has been identified. ANN NEUROL 2025;98:1261-1274.
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