Small molecule inhibitors of TrkB Signaling

项目摘要/摘要 摘要颞叶癫痫(TLE)是一种常见且常具破坏性的人类癫痫类型，缺乏 预防性或疾病修正疗法。据估计，30%的人在有症状的情况下反复发作 使用抗惊厥药物治疗。TLE的一个原因是癫痫持续状态(SE)。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 进行了广泛的靶标验证实验，发现TrkB-PLCγ1是一种可药物分子 可以预防成年小鼠TLE的靶点。我们药物发现计划的目标是开发小分子 TrkB-PLCγ-1信号转导抑制剂治疗TLE在蓝图神经治疗网络的支持下 (BPN)，我们在不同的系列中鉴定了多种化合物，并证明了体内抑制效果 TrkB-PLCγ-1信号在小鼠脑内的表达。我们的具体目标是对小说进行基准测试、扩展和优化 TrkB-PLCγ1信号的小分子抑制剂。成功完成拟议的工作将确定 进入BPN计划发现阶段的领先系列。

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.