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及相关的药理学工具。在这方面，最近的许多 研究清楚地表明，EphA4受体酪氨酸激酶是治疗ALS和 靶向其配体结合结构域可能提供一条新的有效途径 治疗学。基于这些前提，我们最近已经获得了第一个真正的EphA4 靶向其配体结合域的激动剂，这些激动剂是脑穿透的，在脑内具有保护作用 这种疾病的细胞和动物模型。我们的研究旨在进一步优化和表征 本系列将提供关键的药理学工具和对EphA4作用的机械性见解 ALS进展中的调制，在这项研究中收集的数据将对支持 这些药物的发展成为ALS的创新靶向疗法。

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 and associated pharmacological tools. In this regard, numerous recent studies clearly suggest that the EphA4 receptor tyrosine kinase 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 previously recently obtained the first bona fide EphA4 agonistic agents targeting its ligand binding domain, that are brain penetrant and show protection in cellular and animal models of the disease. Our studies aimed at further optimizing and characterizing this series will provide critical pharmacological tools and mechanistic 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.