Small molecule inhibitors of TrkB Signaling

TrkB 信号传导小分子抑制剂

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要颞叶癫痫（TLE）是人类癫痫的一种常见且通常是毁灭性的形式预防或疾病修饰疗法。估计有30％的癫痫发作目的地有症状用抗惊厥药治疗。 TLE的原因之一是状态癫痫症（SE）。定义分子 SE诱导TLE有望鉴定疗法的分子靶标的机制。因此，我们进行了广泛的目标验证实验，该实验揭示了TRKB-PLCγ1作为可药物的分子可以防止成年小鼠TLE的靶标。我们的药物发现计划的目标是开发小分子 TRKB-PLCγ1信号传导的抑制剂以治疗TLE。在蓝图神经疗法网络的支持下（bpn），我们在不同的系列中确定了多种化合物，并证明了体内效率以抑制小鼠脑中的TrkB-PLCγ1信号传导。我们的具体目的是基准，扩展和优化新颖 TRKB-PLCγ1信号传导的小分子抑制剂。成功完成提议的工作将确定进入BPN计划的发现阶段的领先系列。