@article{69da4685716f4c53a4bf1be26aa142f6,
title = "VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons",
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.",
keywords = "KCNT1, MMPSI, Slack channel, epilepsy, inhibitor, small molecule",
author = "Spitznagel, {Brittany D.} and Mishra, {Nigam M.} and Qunies, {Alshaima'A M.} and Prael, {Francis J.} and Yu Du and Kozek, {Krystian A.} and Lazarenko, {Roman M.} and Denton, {Jerod S.} and Emmitte, {Kyle A.} and Weaver, {C. David}",
note = "Funding Information: We thank the laboratory of Dr. Jerod Denton for their supply of the Slo3 plasmid as well as critical discussions. The TREK2 and Ca3.2 cell lines were generously supplied by the laboratories of Dr. David Jacobson and Dr. Simon Xie, respectively. We thank Andrew Glazer and Tim Stassmaier for their help with the use of the Nanion SyncroPatch. We thank Dr. Paige N. Vinson for her descriptions of the HTS libraries. All of the libraries utilized in this work were distributed by the Vanderbilt High-throughput Screening (HTS) Core Facility. Many experiments were performed in the HTS Core with assistance provided by Corbin Whitwell. The WaveGuide screening analysis was assisted by Chris Farmer. Immunofluorescence staining and imaging was assisted by Joshua Bauer and Dr. David Westover. The HTS Core receives support from the Vanderbilt Institute of Chemical Biology and the Vanderbilt Ingram Cancer Center (P30 CA68485). V Funding Information: Funding for this project was provided by National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under the award number 1R21NS109521 and the Vanderbilt Institute of Clinical and Translational Research under the award number VR23772. This research was supported by funds from the Vanderbilt University Pharmacology Department and Vanderbilt Institute of Chemical Biology (C.D.W.). Research funding was also provided through the PhRMA Foundation Pharmacology/Toxicology Predoctoral Fellowship Award (B.D.S.). Funding for the WaveFront Biosciences Panoptic kinetic imaging plate reader and the Syncropatch 768 PE platform was provided by the Office of The Director (OD) of the National Institutes of Health under the award numbers 1S10OD021734 and 1S10OD021734, respectively. The Panoptic and Syncropatch are housed and managed within the Vanderbilt High-throughput Screening Core Facility, an institutionally supported core. Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under award numbers T32GM07628 (B.D.S.), T32GM007347 (K.A.K.), and T32GM065086 (F.J.P.). This research was also supported by funds from the Department of Pharmaceutical Sciences of the UNT System College of Pharmacy (K.A.E.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",
year = "2020",
month = nov,
day = "4",
doi = "10.1021/acschemneuro.0c00583",
language = "English",
volume = "11",
pages = "3658--3671",
journal = "ACS Chemical Neuroscience",
issn = "1948-7193",
publisher = "American Chemical Society",
number = "21",
}