恶性移行性部分性癫痫的婴儿期是罕见的,破坏性形式的癫痫最常见的是与钾通道功能获得突变有关,松弛。这种情况不仅几乎完全耐药,甚至没有选择性的类似药物的工具来评估这些过度激活的抑制,突变型Slack通道可能代表了新的抗癫痫治疗的可行途径。因此,我们使用高通量铊通量测定法来筛选药物样,寻找野生型和疾病相关突变Slack通道的抑制剂的100000个化合物文库。使用这种方法,我们发现了VU0606170,一种选择性Slack通道抑制剂,具有低微摩尔效力。严重的,VU0606170还被证明可以有效地降低过度兴奋时的激发率,自发发射皮质神经元培养物。一起来看,我们的数据提供了令人信服的证据,即小分子可以实现Slack通道活性的选择性抑制,并且抑制神经元中的Slack通道活性产生与抗癫痫作用一致的功效.因此,VU0606170的鉴定提供了一个急需的工具,可促进我们对Slack通道在正常生理和疾病中的作用及其作为治疗干预靶点的潜力的理解.
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.