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.

项目总结/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。TLE的原因之一是癫痫持续状态（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。