Small molecule inhibitors of TrkB Signaling

项目概要/摘要 颞叶癫痫（TLE）是一种常见的和通常具有破坏性的人类癫痫形式， 预防性或疾病改善疗法。估计有30%的人患有复发性癫痫， 用抗惊厥药治疗。癫痫持续状态（SE）是导致TLE的原因之一。定义分子 SE诱导TLE的机制有望确定治疗的分子靶点。因此我们 进行了广泛的靶点验证实验，结果显示TrkB-PLCγ1是一种可药用分子， 可以预防成年小鼠TLE靶点。我们药物发现计划的目标是开发小分子 TrkB-PLCγ1信号传导抑制剂治疗TLE。在Blueprint Neurotherapeutics Network的支持下， (BPN)，我们在不同系列中鉴定了多种化合物，并证明了体内抑制功效 TrkB-PLCγ1信号转导的研究。我们的具体目标是基准，扩展和优化新的 TrkB-PLCγ1信号传导的小分子抑制剂。成功完成拟议的工作将确定一个 进入BPN计划探索阶段的领先系列。

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a common and commonly devastating form of human epilepsy that lacks preventive or disease modifying therapy. An estimated 30% suffer recurrent seizures despite symptomatic treatment with anticonvulsants. One cause of TLE is status epilepticus (SE). Defining the molecular mechanisms by which SE induces TLE promises to identify molecular targets for therapies. We therefore conducted extensive target validation experiments which revealed TrkB-PLCγ1 as a druggable molecular target that can prevent TLE in adult mice. The goal of our drug discovery program is to develop small molecule inhibitors for TrkB-PLCγ1 signaling to treat TLE. With the support of Blueprint Neurotherapeutics Network (BPN), we identified multiple compounds within distinct series with demonstrated in vivo efficacy for inhibition of TrkB-PLCγ1 signaling in mouse brain. Our Specific Aims are to benchmark, expand, and optimize novel small molecule inhibitors of TrkB-PLCγ1 signaling. Successful completion of the work proposed will identify a leading series for entry to the Discovery Phase of BPN program.