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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：
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
项目类别：
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

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. 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