Small molecule in vivo probe development targeting the IL-6/STAT3 pathway for potential multiple sclerosis therapy

针对 IL-6/STAT3 通路的小分子体内探针开发，用于潜在的多发性硬化症治疗

基本信息

批准号：
9057630
负责人：
Chenglong Li
金额：
$ 14.05万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057630
关键词：
Address Adoptive Transfer Adult Antibodies Autoimmune Diseases Autoimmunity Autopsy Binding Biological Assay Biological Availability Biopsy Blocking Antibodies C57BL/6 Mouse CD4 Positive T Lymphocytes Cell Culture Techniques Cells Chemistry Chronic Clinic Clinical Research Colon Complex Data Development Dimerization Disadvantaged Disease Drug Kinetics Effector Cell Elements Enzyme-Linked Immunosorbent Assay Equilibrium Experimental Autoimmune Encephalomyelitis Fc Receptor Flow Cytometry Future Generations Goals Health Hematology Human IL6ST gene Immunocompetent Inflammatory Infusion procedures Injectable Interleukin 6 Receptor Interleukin-17 Interleukin-6 Lead Life Mediating Modeling Molecular Monitor Monoclonal Antibodies Multiple Sclerosis Mus Myelin Neurologic Oral Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Plasma Play Process Production Proteins Reaction Regulatory T-Lymphocyte Relapse Research Resistance Role STAT3 gene Safety Serum Signal Pathway Signal Transduction Specificity Spinal Cord Structure T cell response T-Lymphocyte Tablets Testing Therapeutic Therapeutic Effect Therapeutic antibodies Tissues Toxic effect Toxicity Tests Trauma Umbilical Cord Blood United States base brain tissue capsule cytokine design disability dosage drug candidate drug development effective therapy improved in vivo inhibitor/antagonist innovation mouse model multiple sclerosis patient multiple sclerosis treatment novel prevent repaired response small molecule src Homology Region 2 Domain therapy adherence transcription factor young adult

项目摘要

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is the leading cause of neurologic disability in the United States in young adults after trauma, thus most patients suffer from the effects of MS for most of their adult life. The current MS treatments are partially effective, making it necessary to develop innovative strategies. Interleukin-6 (IL-6), signaling through transcription factor STAT3, shares a central role in multiple pathways of MS pathogenesis and dysregulated IL-6/STAT3 signaling has been shown in MS patients. First, IL-6, signaling through STAT3, induces the generation of highly encephalitogenic IL-17, producing Th17 cells that transfers severe disease in the EAE model of MS. Meanwhile, IL-6 suppresses the generation of inducible T regulatory cells (iTreg), which is critical for dampening pathogenic inflammatory T cell responses. As a result, the Teff/Treg balance is skewed towards excessive T effector responses, favoring the development of autoimmunity. Furthermore, IL-6/STAT3 signaling contributes to the resistance of Teff cells to Treg-mediated suppression in MS patients, which further impairs Teff/Treg balance. Altogether, these studies suggest that the IL-6/STAT3 signaling pathway may serve as an innovative target for reversing pathogenesis in MS patients. In addition, orally available small molecule compounds usually offer improved bioavailability and manufacturing features over commonly used peptide/protein-based drugs. Moreover, therapy adherence is improved when oral agents are used. To this end, we intend to develop small molecule drug candidates targeting IL- 6/STAT3 pathway. We have developed four novel small molecule compounds, MDL-5 and MDL-16 targeting IL-6; LLL-12 and LY-5 targeting STAT3. MDL-5/16 bind to the D1 domain of GP130, preventing the IL-6/GP130 interaction during the hexamerization step of IL-6/IL- 6R/GP130 signaling complex formation; LLL-12/LY-5 bind to the SH2 domain of STAT3, preventing STAT3 phosphorylation and dimerization. When added into cell culture, all four lead compounds significantly inhibit IL-6 induced IL-17 production in myelin-specific CD4 T cells. Based on these previous studies and our preliminary data, we hypothesize that novel small molecule IL-6/STAT3 inhibitors repair the Teff/Treg imbalance of CD4 T responses and suppress disease development and progression in the EAE model of MS. The following aims will address this hypothesis. Aim 1. Optimize the compounds as drug candidates. Aim 2. Determine the effects of novel small molecule IL-6/STAT3 inhibitors on repairing the Teff/Treg imbalance of myelin-specific CD4 T responses and on suppressing disease development in the EAE model of MS. Aim 3. Determine the effects of novel small molecular IL-6/STAT3 inhibitors on repairing Teff/Treg balance in CD4 T cells from MS patients. This study is the first attempt to modulate IL-6/STAT3 signaling using novel small molecules and will elucidate the mechanisms through which IL-6 signaling regulates murine and human CD4 T responses and disease development in vivo in the EAE model of MS. This study will establish the basis for future clinical studies using novel pharmacological compounds that target IL-6/STAT3 signaling, with the ultimate goal of treatment of multiple sclerosis.

描述（由申请人提供）：多发性硬化症 (MS) 是美国年轻人创伤后神经功能障碍的主要原因，因此大多数患者在成年后的大部分时间都受到 MS 的影响。部分有效，因此有必要开发创新策略，通过转录因子 STAT3 发出信号，在 MS 发病机制的多个途径中发挥核心作用，并且在 MS 患者中已显示 IL-6/STAT3 信号失调。。首先，IL-6 通过 STAT3 信号传导，诱导高度致脑炎性 IL-17 的产生，从而产生在 MS 的 EAE 模型中转移严重疾病的 Th17 细胞，同时，IL-6 抑制诱导性 T 调节细胞 (iTreg) 的产生。，这对于抑制致病性炎症 T 细胞反应至关重要，因此，Teff/Treg 平衡倾向于过度 T 效应反应，有利于自身免疫的发展。 IL-6/STAT3 信号传导有助于 MS 患者中 Teff 细胞对 Treg 介导的抑制产生抵抗，从而进一步损害 Teff/Treg 平衡。总而言之，这些研究表明 IL-6/STAT3 信号传导途径可能作为一个创新靶点。此外，与常用的基于肽/蛋白质的药物相比，口服小分子化合物通常具有更高的生物利用度和制造特性。为此，我们使用口服药物可以提高治疗依从性。我们打算开发针对IL-6/STAT3通路的小分子候选药物。我们已经开发了四种新型小分子化合物，即针对IL-6的MDL-5和MDL-16以及针对MDL-5的LY-5。 /16 与 GP130 的 D1 结构域结合，阻止 IL-6/IL-6R/GP130 信号复合物形成的六聚化步骤期间的 IL-6/GP130 相互作用； LLL-12/LY-5 与 STAT3 的 SH2 结构域结合，防止 STAT3 磷酸化和二聚化。当添加到细胞培养物中时，所有四种先导化合物均显着抑制髓磷脂特异性 CD4 T 细胞中 IL-6 诱导的 IL-17 产生。根据这些先前的研究和我们的初步数据，我们寻求新型小分子 IL-6/STAT3 抑制剂修复 CD4 T 反应的 Teff/Treg 失衡，并抑制 MS 的 EAE 模型中的疾病发生和进展。以下目标将解决这一假设。目标 1. 优化作为候选药物的化合物目标 2. 确定新型小分子 IL-6/STAT3 抑制剂对修复髓磷脂特异性 CD4 T 反应的 Teff/Treg 失衡的影响。目的 3. 确定新型小分子 IL-6/STAT3 抑制剂对修复 MS 患者 CD4 T 细胞中 Teff/Treg 平衡的影响。这项研究是首次尝试使用新型小分子调节 IL-6/STAT3 信号传导，并将阐明 IL-6 信号传导在 MS 的 EAE 模型中调节小鼠和人类 CD4 T 反应和体内疾病发展的机制。为未来使用针对 IL-6/STAT3 信号传导的新型药理化合物进行临床研究奠定基础，最终目标是治疗多发性硬化症。