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

• 批准号: 9977007
• 负责人: Maurizio Pellecchia
• 金额: $ 45.17万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 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/9977007
• 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; Treatment Efficacy; Untranslated RNA; X-Ray Crystallography; 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

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.

摘要 肌萎缩侧索硬化症(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号染色体的突变似乎是最常见的 在那些受疾病影响的人身上。尽管做出了巨大的努力来确定促成因素 对于肌萎缩侧索硬化症，运动神经元死亡的机制尚未完全阐明， 因此，目前还没有有效的治疗ALS的方法。已经有几项临床试验 然而，这些药物是基于从动物研究中挑选出来的药物而启动的，最终失败了。显然， 这些失败的可能原因之一是缺乏适当的药物靶点来负责 肌萎缩侧索硬化症的发病和进展。在这方面，最近的许多研究清楚地表明，EphA4是一种 ALS的潜在药物靶点及其配体结合域可能提供一种可能的 通向新颖有效的治疗方法的大道。基于这些前提，我们最近设计和 合成了一种新型EphA4结合剂，命名为123C4，靶向其配体结合域123C4 对EphA4受体表现出纳摩尔亲和力，其选择性是最接近的受体的10倍 该家族(EphA3)是脑穿透性的，在SOD1突变小鼠模型中显示出显著的疗效 肌萎缩侧索硬化。我们旨在进一步优化和描述这一系列的研究将提供关键的见解 关于EphA4在ALS进展中的作用，本研究收集的数据将 在支持这些药物发展成为ALS的创新靶向疗法方面发挥关键作用。