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

• 批准号: 8887773
• 负责人: Chenglong Li
• 金额: $ 47.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887773
• 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; Hematology; Human; 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; novel; prevent; public health relevance; repaired; response; small molecule; src Homology Region 2 Domain; therapy adherence; transcription factor; young adult

 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.