Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome
Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome
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DOI：
10.1007/s11095-019-2671-y
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发表时间：
2019-09-01
影响因子：
3.7
通讯作者：
Gerlach, Aaron
中科院分区：
文献类型：
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作者：
Ekins, Sean;Gerlach, Jacob;Gerlach, Aaron
目的皮特-霍普金斯综合征(PTHS)是一种罕见的遗传性疾病，由位于18号染色体上的转录因子4(TCF4)基因突变引起。PTHS可导致中度至重度智能障碍，大多数患者表现为精神运动迟缓。PTHS还表现出自闭症谱系障碍的特征，其特征是沟通和社交能力受损。PTHS与癫痫发作的高患病率并存，癫痫发作可能从出生起就存在，或者通常在儿童时期发展。减弱或缺失TCF4的表达导致外周离子通道K(V)7.1和Na(V)1.8的翻译增加，从而触发后超极化的增加和激发特性的改变。方法我们现在描述一个高通量筛选(HTS)，其中包括1280种批准的药物和根据这些数据开发的机器学习模型。离子通道在CHO(K(V)7.1)或HEK293(Na(V)1.8)细胞中表达，HTS使用Rb-86(+)外排(K(V)7.1)或FLIPR分析(Na(V)1.8)。结果HTS在10mU的筛选浓度下提供了55种K(V)7.1的抑制剂(4.2%命中率)和93种Na(V)1.8的抑制剂(7.2%命中率)。这些数据集也使我们能够建立和验证这些离子通道的贝叶斯机器学习模型。我们还描述了几种二氢吡啶类化合物作为Na(V)1.8抑制剂的构效关系。结论尼卡地平或其他二氢吡啶类钙通道拮抗剂可能会被重新用于通过Na(V)1.8作用于PTHS的潜在治疗，因为目前还没有批准的治疗这种罕见疾病的药物。
PurposePitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K(v)7.1 and Na(v)1.8 which triggers an increase in after-hyperpolarization and altered firing properties.MethodsWe now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K(V)7.1) or HEK293 (Na(v)1.8) cells and the HTS used either Rb-86(+) efflux (K(V)7.1) or a FLIPR assay (Na(v)1.8).ResultsThe HTS delivered 55 inhibitors of K(v)7.1 (4.2% hit rate) and 93 inhibitors of Na(v)1.8 (7.2% hit rate) at a screening concentration of 10 mu M. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Na(v)1.8.ConclusionsThis work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na(v)1.8, as there are currently no approved treatments for this rare disorder.