Development of drugs that modify CNS innate immunity for the treatment of Multiple Sclerosis

开发改变中枢神经系统先天免疫的药物来治疗多发性硬化症

• 批准号: 10434315
• 负责人: Kevin Hodgetts
• 金额: $ 43.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434315
• 关键词: Amides; Astrocytes; Axon; Back; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Diseases; Clinical; Crystallization; Crystallography; Cuprizone; Data; Demyelinations; Development; Disease; Dose; Drug Design; Eph Family Receptors; Erythropoietin; Evaluation; Experimental Autoimmune Encephalomyelitis; Experimental Models; Flow Cytometry; Gene Expression Profiling; Goals; Histopathology; Human; Image; In Vitro; Inbred NOD Mice; Industry; Inflammation; Inflammatory; Lead; Magnetic Resonance; Microglia; Modeling; Modification; Multiple Sclerosis; Mus; Natural Immunity; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurologic; Oral; Pathogenesis; Pathogenicity; Pathologic Processes; Pathology; Pathway interactions; Penetration; Periodicity; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Play; Positioning Attribute; Pre-Clinical Model; Primary carcinoma of the liver cells; Property; Proteins; Regulation; Role; Secondary Progressive Multiple Sclerosis; Signal Transduction; Solubility; Specificity; Structure; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Treatment Efficacy; United States National Institutes of Health; analog; aqueous; base; brain tissue; design; disability; drug development; efficacious treatment; efficacy testing; in vitro Assay; in vitro testing; in vivo; inhibitor; interest; kinase inhibitor; monocyte; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nervous system development; nervous system disorder; novel; piperidine; preclinical development; predictive test; pyridine; receptor; recruit; response; targeted treatment; therapeutic candidate; therapeutic lead compound; therapeutic target; therapy development; tool; Amides; Astrocytes; Axon; Back; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Diseases; Clinical; Crystallization; Crystallography; Cuprizone; Data; Demyelinations; Development; Disease; Dose; Drug Design; Eph Family Receptors; Erythropoietin; Evaluation; Experimental Autoimmune Encephalomyelitis; Experimental Models; Flow Cytometry; Gene Expression Profiling; Goals; Histopathology; Human; Image; In Vitro; Inbred NOD Mice; Industry; Inflammation; Inflammatory; Lead; Magnetic Resonance; Microglia; Modeling; Modification; Multiple Sclerosis; Mus; Natural Immunity; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurologic; Oral; Pathogenesis; Pathogenicity; Pathologic Processes; Pathology; Pathway interactions; Penetration; Periodicity; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Play; Positioning Attribute; Pre-Clinical Model; Primary carcinoma of the liver cells; Property; Proteins; Regulation; Role; Secondary Progressive Multiple Sclerosis; Signal Transduction; Solubility; Specificity; Structure; Structure-Activity Relationship; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Treatment Efficacy; United States National Institutes of Health; analog; aqueous; base; brain tissue; design; disability; drug development; efficacious treatment; efficacy testing; in vitro Assay; in vitro testing; in vivo; inhibitor; interest; kinase inhibitor; monocyte; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nervous system development; nervous system disorder; novel; piperidine; preclinical development; predictive test; pyridine; receptor; recruit; response; targeted treatment; therapeutic candidate; therapeutic lead compound; therapeutic target; therapy development; tool

PROJECT SUMMARY Pathology driven by resident cells in the central nervous system (CNS) such as astrocytes and microglia plays an important role in multiple sclerosis (MS), particularly for its progressive stage which is eventually achieved by most MS patients. However, no drugs are available for the modulation astrocyte and microglia pathogenic activities. We developed an in vitro assay to identify compounds that modulate astrocyte pathogenic activities. These studies identified compound A-38, an inhibitor of the Erythropoietin-producing hepatocellular carcinoma receptor B3 (EphB3), as a suppressor of astrocyte pathogenic activities and, consequently, as a lead therapeutic compound for progressive MS (PMS). Moreover, our data suggest that microglia-driven EphB3 signaling in astrocytes promotes CNS inflammation and neurodegeneration. Ephrin receptors are known to participate in CNS development, however our findings define a novel role for EphB3 in CNS inflammation and identify it as potential target for therapeutic intervention. We hypothesize that EphB3 kinase inhibition will provide an efficacious therapeutic approach for PMS, and potentially other neurologic diseases. Thus, we propose to develop new A-38 analogs to treat PMS. Our Specific Aims are: SPECIFIC AIM 1: OPTIMIZATION AND IN VITRO EVALUATION OF EPHB3 KINASE INHIBITORS. We will design, synthesize and evaluate the properties of up to 150 analogs of A-38. The goal of these studies is to optimize the potency and kinase selectivity of new analogs of A-38, while maintaining good drug-like properties and brain exposure following oral delivery. During the R61 phase of this project, we will integrate iterative structure-activity relationship (SAR) studies and structure based drug design to optimize A-38 potency and kinase selectivity, while maintaining good drug-like properties. We will first evaluate A-38 analogs for EphB3 activity and for selectivity in EphB2 EphB4, and EphA4 kinase assays. Promising compounds will advance to phenotypic assays to identify those molecules that modulate astrocyte pathogenic activities. Compounds of interest will then be characterized in drug-like property assays to select leading compounds for PO PK studies. At the end of the R61 phase of this project we expect to identify a lead EphB3 inhibitor and 1-2 back-ups suitable for advancement into in vivo efficacy testing in the R33 phase. SPECIFIC AIM 2: EVALUATION OF LEAD COMPOUND(S) IN PMS PRE-CLINICAL MODELS. During the R33 phase of this project, we will evaluate the lead EphB3 inhibitor and 1-2 back-ups in the NOD EAE and cuprizone-induced murine pre-clinical models which recapitulate several aspects of PMS. We will evaluate the effects of the compounds on disease development, CNS inflammation, axonal loss and demyelination, as determined by histopathology, flow cytometry and gene expression analyses. In summary, this project will identify a novel EphB3 inhibitor with drug-like properties suitable for development as a candidate therapeutic for PMS and other neurologic diseases with NIH and/or industry support.

项目摘要 由中枢神经系统（CNS）中的居民细胞（例如星形胶质细胞和小胶质细胞游戏）驱动的病理学 在多发性硬化症（MS）中的重要作用，尤其是在其渐进阶段最终实现的阶段 大多数MS患者。但是，没有药物可用于调节星形胶质细胞和小胶质细胞致病性 活动。我们开发了一种体外测定，以鉴定调节星形胶质病原活性的化合物。 这些研究确定了产生促红细胞生成素的肝细胞的化合物A-38 癌受体B3（EPHB3），作为星形胶质细胞致病活性的抑制剂，因此是 进行性MS（PMS）的铅治疗化合物。此外，我们的数据表明小胶质细胞驱动 星形胶质细胞中的EPHB3信号传导促进CNS炎症和神经退行性。 ephrin受体是 已知会参与CNS开发，但是我们的发现定义了CNS中EPHB3的新作用 炎症并将其确定为治疗干预的潜在靶标。我们假设EPHB3 激酶抑制作用将为PM提供有效的治疗方法，并可能为其他 神经疾病。因此，我们建议开发新的A-38类似物来治疗PM。我们的具体目的是： 具体目标1：EPHB3激酶抑制剂的优化和体外评估。我们将 设计，合成和评估A-38多达150个类似物的特性。这些研究的目的是 优化A-38的新类似物的效力和激酶选择性，同时保持良好的类似药物样性能 和口服输送后的大脑暴露。在该项目的R61阶段，我们将整合迭代 结构活性关系（SAR）研究和基于结构的药物设计，以优化A-38效力和 激酶选择性，同时保持良好的类似药物样特性。我们将首先评估EPHB3的A-38类似物 EPHB2 EPHB4和EPHA4激酶测定中的活性和选择性。有希望的化合物将发展到 表型测定方法以识别那些调节星形胶质病原活性的分子。化合物的 然后将在类似药物的特性测定中进行兴趣，以选择用于PO PK研究的主要化合物。 在该项目的R61阶段结束时，我们希望识别铅EPHB3抑制剂和1-2个备份 适合在R33阶段进步到体内功效测试。 特定目标2：PMS临床前模型中铅化合物的评估。在 该项目的R33阶段，我们将评估铅EPHB3抑制剂和1-2个备份。 Cuprizone诱导的鼠前模型概括了PM的几个方面。我们将评估 这些化合物对疾病发育，CNS炎症，轴突丧失和脱髓鞘的影响， 由组织病理学，流式细胞术和基因表达分析确定。 总而言之，该项目将识别具有适合开发的药物样特性的新型EPHB3抑制剂 作为NIH和/或行业支持的PMS和其他神经系统疾病的候选治疗。