Slack Potassium Channel Inhibitors for the Treatment of Childhood Epilepsies

用于治疗儿童癫痫的松弛钾通道抑制剂

基本信息

批准号：
10037654
负责人：
Kyle A Emmitte
金额：
$ 43.45万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10037654
关键词：
Action Potentials Advanced Development Affect Antiepileptic Agents Biological Assay Cell Line Cell Volumes Cell division Cell membrane Cells Cellular Assay Data Development Disease Drug Kinetics Drug resistance Electrophysiology (science)Epilepsy Equilibrium Family Family member Foundations Genes Goals Hand Heart High-Throughput Nucleotide Sequencing Hormone secretion In Vitro Individual Infrastructure Ion Channel Ions Lead Libraries Life Mediating Membrane Potentials Mutation NAD-Binding Domain Nervous system structure Nucleic Acid Regulatory Sequences Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Physiological Play Potassium Channel Property Quinidine Regulation Research Role Signal Transduction Structure Structure-Activity Relationship Testing Therapeutic United States Variant base biobank childhood epilepsy course development design disabling symptom drug discovery drug metabolism effective therapy falls gain of function gain of function mutation in vivo infancy inhibitor/antagonist lead optimization malignant migrating partial seizures of infancy member mutant scaffold screening small molecule solute sperm cell tool voltage clamp water channel

项目摘要

ABSTRACT Potassium channels are critical for life, playing a variety of physiological roles including control of solute balance, cell volume, and cellular excitability. In excitable cells potassium channels are involved in setting membrane potential and modulation of action potentials. Slack channels, encoded by KCNT1, are members of the Slo family of potassium channels, comprised of Slo1 (Maxi-K), Slo2.1 (Slick), Slo2.2 (Slack) and Slo3, a sperm-specific channel. Recently, multiple studies have identified ~30 mutations in Slack channels that are associated with a variety of epilepsies, most frequently Malignant Migrating Partial Seizures of Infancy (MMPSI). MMPSI are extremely severe, pharmacoresistant, and typically fatal during the first year of life. Slack variants associated with these epilepsies are found in three clusters: the pore of the channel, and in two separate carboxy-terminal regulatory regions, Regulator of Conductance of K+ (RCK) and NAD+ binding domains. Interestingly, these mutations are dominant, gain-of-function mutations resulting in a higher degree of Slack channel activity. Although the exact mechanism by which over-activity of Slack leads to MMPSI and other, less severe epilepsies is not understood, we hypothesize that specific inhibitors of Slack channels may provide a viable anti-epileptic strategy. Thus, the aims of this proposal are to build a hit-discovery and characterization infrastructure focused on providing an ability to conduct an 110,000 compound screen on wild-type Slack and 3 MMPSI-associated mutants, one from each of the three clusters (R21 Phase). We will utilize this infrastructure and a focused hit-to- leads medicinal-chemistry effort, including assays and strategies geared toward enhancing drug-likeness, to support the discovery and characterization of Slack-specific inhibitors (R33 Phase). The goal of the proposed research is to discover and validate at least two small molecule scaffolds, providing a platform for development of in vivo-active Slack inhibitors and a foundation for a therapeutically focused lead optimization effort.

抽象的钾通道对生活至关重要，扮演多种生理角色，包括控制溶质平衡，细胞体积和细胞兴奋性。在可激发的细胞中动作电位的潜在和调节。由KCNT1编码的松弛频道是SLO家族的成员由Slo1（Maxi-K），Slo2.1（Slick），Slo2.2（Slack）和Slo3组成的钾通道的钾通道渠道。最近，多项研究发现了与A的松弛通道中约30个突变，这些突变与A 各种癫痫症，最常见的是恶性迁移的婴儿期癫痫发作（MMPSI）。 mmpsi是极度严重，药剂敏感，通常在生命的第一年致命。相关的松弛变体与这些癫痫发作的三个簇中可以找到：通道的孔，以及两个单独的羧基末端调节区域，K+（RCK）和NAD+结合域的电导率调节剂。有趣的是，这些突变是主导的，功能增益突变，导致较高程度的松弛通道活性。尽管松弛过度活跃导致MMPSI和其他少量癫痫的确切机制尚不理解，我们假设松弛通道的特定抑制剂可能会提供可行的抗癫痫战略。因此，该提案的目的是建立以重点为重点提供在野生型松弛和3 mmpsi相关的能力上进行110,000个复合屏幕突变体，三个簇中的每个（R21相）。我们将利用此基础架构以及专注的命中率领导药物化学工作，包括旨在增强毒品的测定和策略支持松弛特异性抑制剂（R33期）的发现和表征。提议的目标研究是要发现和验证至少两个小分子支架，为开发提供了一个平台体内活性的松弛抑制剂和治疗剂量铅优化工作的基础。