Targeting the EPhA4 in motor neuron disease: a structure-based approach

运动神经元疾病中的靶向 EPhA4：基于结构的方法

基本信息

批准号：
10413844
负责人：
Maurizio Pellecchia
金额：
$ 45.02万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413844
关键词：
ALS patients Affect Affinity Agonist Amyotrophic Lateral Sclerosis Animal Disease Models Animals Astrocytes Astrocytosis Binding Biological Assay Brain C9ORF72 Cell Line Cells Cellular Assay Chromosome 9 Clinical Research Clinical Trials Data Degenerative Disorder Development Disease Disease Progression Drug Targeting EphA4 Receptor Exhibits Failure Family Genes Laboratories Lead Ligand Binding Domain Ligands Mediating Modeling Motor Neuron Disease Motor Neurons Mutation NMR Spectroscopy Names Neurons Pediatric Hospitals Pharmaceutical Preparations Pharmacology Study Plasma Procedures Property Publications Research Institute Role Series Signal Transduction Structure System Testing Transgenic Organisms Untranslated RNA X-Ray Crystallography antagonist base biophysical techniques cellular imaging combinatorial chemistry design drug candidate effective therapy follow-up in vivo innovation insight lead optimization molecular modeling mouse model mutant mouse model nanomolar neuron loss new therapeutic target novel receptor superoxide dismutase 1 targeted agent targeted treatment therapeutically effective

项目摘要

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease that affects motor neurons. Mutations in the gene SOD1 (superoxide dismutase 1) and in chromosome 9 seem the most prevalent in those affected by the disease. Despite tremendous efforts aimed at identifying contributing factors for ALS, the mechanisms underlying motor neuron death have not yet been fully elucidated and consequently no effective treatment is currently available for ALS. Several clinical trials have been initiated based on drugs selected from animal studies, however, these ultimately failed. Obviously among the possible reasons for such failures, is the lack of a proper drug target responsible for the onset and progression of ALS. In this regard, numerous recent studies clearly suggest the EphA4 is a potential drug target for ALS and that targeting its ligand–binding domain may provide a possible avenue to novel and effective therapeutics. Based on these premises, we have recently designed and synthesized a novel EphA4 binding agent, named 123C4, targeting its ligand binding domain 123C4 exhibits nanomolar affinity for the EphA4 receptor with > 10 fold selectivity over the closest receptor of the family (EphA3), are brain penetrant and show notable efficacy in a SOD1 mutant mouse model of ALS. Our studies aimed at further optimizing and characterizing this series will provide critical insights on the role of the EphA4 modulation in the progression of ALS, and the data gathered in this study will be critical in supporting the development of these agents into innovative targeted therapeutics for ALS.

抽象的肌萎缩性侧索硬化症（ALS）是一种影响运动神经元的进行性退行性疾病。基因SOD1（超氧化物歧化酶1）和9染色体中的突变似乎是最普遍的在受疾病影响的人中。尽管旨在确定促成因素的巨大努力对于ALS，运动神经元死亡的基础机制尚未完全阐明，并且因此，目前尚无有效的治疗方法。几个临床试验已经但是，根据从动物研究中选择的药物开始，这些药物最终失败了。明显地这种失败的可能原因之一是缺乏负责的适当药物靶标 ALS的发作和进展。在这方面，许多最近的研究清楚地表明epha4是 ALS的潜在药物靶标和靶向其配体结合域可能会提供可能新颖有效疗法的途径。基于这些前提，我们最近设计了合成了一种新型的Epha4结合剂，称为123C4，靶向其配体结合域123C4 表现出对EPHA4受体的纳摩尔亲和力，其在闭合受体上的选择性> 10倍家族（Epha3）是大脑渗透物，在SOD1突变小鼠模型中显示出明显的效率 ALS。我们的研究旨在进一步优化和表征该系列的研究将提供关键的见解关于EPHA4调制在ALS进展中的作用，本研究中收集的数据将对于支持这些代理的创新目标治疗ALS的发展至关重要。