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

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SOD 1（超氧化物歧化酶1）和9号染色体上的突变似乎是最普遍的 在那些受疾病影响的人身上。尽管作出了巨大努力， 对于ALS，运动神经元死亡的潜在机制尚未完全阐明， 因此，目前还没有有效的治疗ALS的方法。一些临床试验已经 基于从动物研究中选择的药物开始，然而，这些最终失败了。显然 这些失败的可能原因之一是缺乏适当的药物靶点， ALS的发病和进展。在这方面，许多最近的研究清楚地表明EphA4是一种 ALS的潜在药物靶点，靶向其配体结合结构域可能提供一种可能的 新的和有效的治疗方法的途径。基于这些前提，我们最近设计并 合成了一种新的EphA4结合剂，命名为123C4，靶向其配体结合结构域123C4 对EphA4受体表现出纳摩尔亲和力，其选择性超过最接近的EphA4受体> 10倍。 该家族（EphA3）是脑渗透剂，并在SOD1突变小鼠模型中显示出显著功效， 人症我们的研究旨在进一步优化和表征这一系列将提供关键的见解 EphA4调节在ALS进展中的作用，本研究中收集的数据将 在支持这些药物发展成为ALS的创新靶向治疗药物方面至关重要。

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.