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

基本信息

批准号：
10606625
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
项目类别：
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/10606625
关键词：
Amides Astrocytes Axon Binding Biological Assay Blood - brain barrier anatomy Brain Cells Central Nervous System 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 Microsomes Modeling Modification Multiple Sclerosis Mus Natural Immunity Nerve Degeneration Nervous System Physiology 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 Progressive Multiple Sclerosis 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 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

项目摘要

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.

项目概要由中枢神经系统 (CNS) 中的常驻细胞（如星形胶质细胞和小胶质细胞）驱动的病理学在多发性硬化症 (MS) 中发挥重要作用，尤其是最终达到的进展阶段大多数多发性硬化症患者。然而，目前尚无药物可用于调节星形胶质细胞和小胶质细胞的致病性。活动。我们开发了一种体外测定法来鉴定调节星形胶质细胞致病活性的化合物。这些研究鉴定出化合物 A-38，一种促红细胞生成素生成肝细胞的抑制剂癌受体 B3 (EphB3)，作为星形胶质细胞致病活性的抑制剂，因此，作为一种用于进行性多发性硬化症 (PMS) 的先导治疗化合物。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 信号传导促进中枢神经系统炎症和神经退行性变。肝配蛋白受体是已知参与 CNS 发育，但我们的研究结果定义了 EphB3 在 CNS 中的新作用炎症并将其确定为治疗干预的潜在目标。我们假设 EphB3 激酶抑制将为经前综合症和其他潜在的疾病提供有效的治疗方法神经系统疾病。因此，我们建议开发新的 A-38 类似物来治疗经前综合症。我们的具体目标是：具体目标 1：EPHB3 激酶抑制剂的优化和体外评价。我们将设计、合成和评估多达 150 种 A-38 类似物的特性。这些研究的目标是优化 A-38 新类似物的效力和激酶选择性，同时保持良好的药物样特性以及口服给药后的大脑暴露。在这个项目的R61阶段，我们将整合迭代构效关系 (SAR) 研究和基于结构的药物设计，以优化 A-38 的效力和激酶选择性，同时保持良好的药物特性。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。有前景的化合物将推进到表型测定来鉴定调节星形胶质细胞致病活性的分子。的化合物然后将通过类药特性测定来表征兴趣，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，我们期望确定一种主要的 EphB3 抑制剂和 1-2 个备用抑制剂适合进入R33阶段的体内功效测试。具体目标 2：评估 PMS 临床前模型中的先导化合物。期间在该项目的 R33 阶段，我们将评估 NOD EAE 中的主要 EphB3 抑制剂和 1-2 个备用药物铜宗诱导的小鼠临床前模型概括了经前综合症的几个方面。我们将评估这些化合物对疾病发展、中枢神经系统炎症、轴突损失和脱髓鞘的影响，如通过组织病理学、流式细胞术和基因表达分析确定。总之，该项目将鉴定出一种具有类似药物特性、适合开发的新型 EphB3 抑制剂在 NIH 和/或行业支持下作为经前综合症和其他神经系统疾病的候选疗法。