VU0606170, a Selective Slack Channels Inhibitor, Decreases Calcium Oscillations in Cultured Cortical Neurons
Brittany D Spitznagel1, Nigam M Mishra2, Alshaima'a M Qunies2,3
1Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States.
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.
Insights
Researchers identified VU00606170, a novel small molecule, that selectively inhibits Slack channels. This discovery offers a potential new therapeutic strategy for malignant migrating partial seizures of infancy, a severe form of epilepsy.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Malignant migrating partial seizures of infancy (MMPE) is a rare epilepsy syndrome.
- MMPE is often caused by gain-of-function mutations in the Slack potassium channel.
- Current treatments for MMPE are largely ineffective, and specific pharmacological tools are lacking.
Purpose of the Study:
- To screen for selective inhibitors of wild-type and mutant Slack channels.
- To identify potential therapeutic agents for MMPE.
- To develop a tool compound for studying Slack channel function in epilepsy.
Main Methods:
- High-throughput thallium flux assay screening of a 100,000-compound library.
- Testing identified compounds for inhibition of wild-type and mutant Slack channels.
- Evaluating the efficacy of inhibitors in reducing neuronal firing rates in cortical neuron cultures.
Main Results:
- Discovery of VU00606170, a selective Slack channel inhibitor with low micromolar potency.
- VU00606170 significantly reduced neuronal firing rates in overexcited cortical neuron cultures.
- Demonstrated that small molecules can selectively inhibit Slack channel activity.
Conclusions:
- Selective inhibition of Slack channel activity is achievable with small molecules.
- Inhibiting Slack channel activity in neurons shows promise for antiepileptic effects.
- VU00606170 is a valuable tool for investigating Slack channel roles in physiology and disease, and for developing new epilepsy therapies.
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