VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons

Brittany D. Spitznagel, Nigam M. Mishra, Alshaima'A M. Qunies, Francis J. Prael, Yu Du, Krystian A. Kozek, Roman M. Lazarenko, Jerod S. Denton, Kyle A. Emmitte, C. David Weaver

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Malignant migrating partial seizures of infancy is a rare, devastating form of epilepsy most commonly associated with gain-of-function mutations in the potassium channel, Slack. Not only is this condition almost completely pharmacoresistant, there are not even selective drug-like tools available to evaluate whether inhibition of these overactivated, mutant Slack channels may represent a viable path forward toward new antiepileptic therapies. Therefore, we used a high-throughput thallium flux assay to screen a drug-like, 100 »000-compound library in search of inhibitors of both wild-type and a disease-associated mutant Slack channel. Using this approach, we discovered VU0606170, a selective Slack channel inhibitor with low micromolar potency. Critically, VU0606170 also proved effective at significantly decreasing the firing rate in overexcited, spontaneously firing cortical neuron cultures. Taken together, our data provide compelling evidence that selective inhibition of Slack channel activity can be achieved with small molecules and that inhibition of Slack channel activity in neurons produces efficacy consistent with an antiepileptic effect. Thus, the identification of VU0606170 provides a much-needed tool for advancing our understanding of the role of the Slack channel in normal physiology and disease as well as its potential as a target for therapeutic intervention.

Original languageEnglish
Pages (from-to)3658-3671
Number of pages14
JournalACS Chemical Neuroscience
Volume11
Issue number21
DOIs
StatePublished - 4 Nov 2020

Keywords

  • KCNT1
  • MMPSI
  • Slack channel
  • epilepsy
  • inhibitor
  • small molecule

Fingerprint Dive into the research topics of 'VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons'. Together they form a unique fingerprint.

Cite this