Small molecule inhibitors of TrkB Signaling

TrkB 信号传导小分子抑制剂

• 批准号: 10727579
• 负责人: James O. McNamara
• 金额: $ 42.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727579
• 关键词: Adult; Anticonvulsants; Autoimmune; Behavior assessment; Benchmarking; Binding Proteins; Biological Assay; Biological Markers; Brain; Cells; Central Nervous System Diseases; Cessation of life; Clinical Research; Development; Disadvantaged; Disease; Dose; Drug Kinetics; Epilepsy; Epileptogenesis; Exhibits; Goals; Human; In Vitro; Lead; Measures; Mediating; Medical; Mission; Modeling; Molecular; Molecular Target; Mus; National Institute of Neurological Disorders and Stroke; Nervous System; Neuronal Injury; Neurotrophic Tyrosine Kinase Receptor Type 2; PLC gamma1; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphotransferases; Plasma; Preventive; Property; Proteins; Public Health; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Recurrence; Sampling; Seizures; Series; Signal Pathway; Signal Transduction; Solubility; Status Epilepticus; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Therapeutic; Thiourea; Time; Validation; Work; anxiety-like behavior; aqueous; brief intervention; chemical genetics; comorbidity; design; drug discovery; drug modification; efficacy evaluation; experimental study; genetic approach; improved; in vivo; inhibitor; innovation; insight; lead series; molecular targeted therapies; neuroprotection; novel; pharmacokinetics and pharmacodynamics; preclinical study; prevent; programs; small molecule inhibitor; symptom treatment

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.

项目概要/摘要 颞叶癫痫 (TLE) 是人类癫痫的一种常见且具有破坏性的形式 尽管有症状，但估计有 30% 的患者仍会出现癫痫发作。 TLE 的病因之一是癫痫持续状态 (SE)。 SE 诱导 TLE 的机制有望确定治疗的分子靶点。 进行了广泛的靶点验证实验，结果表明 TrkB-PLCγ1 是一种可成药的分子 我们的药物发现计划的目标是开发小分子。 在 Blueprint Neurotherapeutics Network 的支持下，TrkB-PLCγ1 信号抑制剂用于治疗 TLE。 (BPN)，我们鉴定了不同系列中的多种化合物，这些化合物被证明具有体内抑制功效 我们的具体目标是对小鼠大脑中的 TrkB-PLCγ1 信号进行基准测试、扩展和优化。 TrkB-PLCγ1 信号传导的小分子抑制剂 成功完成所提出的工作将确定一个 进入 BPN 计划发现阶段的领先系列。