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：
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
项目类别：
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

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 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.

抽象的肌萎缩侧索硬化症 (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普遍的尽管为确定影响因素付出了巨大的努力。对于 ALS，运动神经元死亡的机制尚未完全阐明，因此，目前还没有针对 ALS 的有效治疗方法，已经进行了多项临床试验。基于动物研究中选定的药物发起的，然而，这些最终失败了。造成此类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有许多研究。研究明确表明 EphA4 受体酪氨酸激酶是 ALS 的潜在药物靶点靶向其配体结合域可能为新颖有效的研究提供可能的途径基于这些前提，我们最近获得了第一个真正的EphA4。靶向其配体结合域的激动剂，具有脑渗透性并在我们的研究旨在进一步优化和表征该疾病的细胞和动物模型。该系列将提供关于 EphA4 作用的关键药理学工具和机制见解 ALS 进展的调节，本研究收集的数据对于支持将这些药物开发成 ALS 的创新靶向疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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