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: 10736509
• 负责人: Maurizio Pellecchia
• 金额: $ 40.85万
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736509
• 关键词: ALS patients; Affect; Affinity; Amyotrophic Lateral Sclerosis; Animal Disease Models; Animal Model; Animals; Astrocytes; Astrocytosis; Binding; Brain; C9ORF72; COVID-19 pandemic; Cell model; Cells; Cellular Assay; Chromosome 9; Clinical Research; Clinical Trials; Complex; Data; Degenerative Disorder; Development; Digit structure; Disease; Disease Progression; Dose; Drug Targeting; EphA4 Receptor; Failure; Family; Foundations; Genes; In Vitro; Laboratories; Lead; Ligand Binding Domain; Ligands; Medical; Microsomes; Modeling; Motor Neuron Disease; Motor Neurons; Mus; Mutation; Names; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Pharmacology Study; Plasma; Property; Rattus; Research Institute; Resolution; Roentgen Rays; Role; Series; Signal Transduction; Solubility; Structure; Testing; Therapeutic; Time; Transgenic Organisms; Untranslated RNA; aqueous; combinatorial chemistry; design; drug candidate; effective therapy; familial amyotrophic lateral sclerosis; follow-up; improved; in vivo; innovation; insight; lead optimization; mouse model; mutant; nanomolar; neuron loss; new therapeutic target; novel; pharmacologic; sporadic amyotrophic lateral sclerosis; superoxide dismutase 1; targeted agent; targeted treatment; therapeutically effective; tool

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.

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发起，然而，这些最终失败了。显然 这种失败的可能原因之一是缺乏适当的药物靶点， ALS的发病和进展以及相关的药理学工具。在这方面，最近许多 研究清楚地表明EphA4受体酪氨酸激酶是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途径， 治疗学基于这些前提，我们之前最近获得了第一个真正的EphA4 靶向其配体结合结构域的激动剂是脑渗透剂， 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EphA4作用的机制见解 调节ALS的进展，这项研究中收集的数据将是关键的支持， 将这些药物开发成ALS的创新靶向治疗药物。

项目成果

EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis -astrocytes.

• DOI: 10.1016/j.isci.2022.104877
• 发表时间: 2022-09-16
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Dennys, Cassandra;Baggio, Carlo;Rodrigo, Rochelle;Roussel, Florence;Kulinich, Anna;Heintzman, Sarah;Fox, Ashley;Kolb, Stephen J.;Shaw, Pamela J.;Ethell, Iryna M.;Pellecchia, Maurizio;Meyer, Kathrin C.
• 通讯作者: Meyer, Kathrin C.

CuATSM effectively ameliorates ALS patient astrocyte-mediated motor neuron toxicity in human in vitro models of amyotrophic lateral sclerosis.

• DOI: 10.1002/glia.24278
• 发表时间: 2023-02
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Dennys, Cassandra N.;Roussel, Florence;Rodrigo, Rochelle;Zhang, Xiaojin;Delgado, Andrea Sierra;Hartlaub, Annalisa;Saelim-Ector, Asya;Ray, Will;Heintzman, Sarah;Fox, Ashley;Kolb, Stephen J.;Beckman, Joseph;Franco, Maria Clara;Meyer, Kathrin
• 通讯作者: Meyer, Kathrin