Blocking a novel cytokine signaling pathway for the treatment of rheumatoid arthr

阻断新的细胞因子信号通路治疗类风湿关节炎

• 批准号: 8590957
• 负责人: Kirill Ostanin
• 金额: $ 14.53万
• 依托单位: NAVIGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2014-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8590957
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Adverse event; Affect; B-Lymphocytes; Binding; Biochemical; Biological; Biological Assay; Blood Vessels; Cardiovascular system; Categories; Cell model; Cellular Assay; Characteristics; Chemicals; Chronic; Collaborations; Cytokine Network Pathway; Cytokine Receptors; Cytokine Signaling; Data; Development; Disease; Drug Kinetics; Endothelial Cells; Endothelium; Equilibrium; Evaluation; Event; Extravasation; Exudative age-related macular degeneration; Future; Goals; Grant; Guanosine Triphosphate; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammation Process; Inflammatory; Inflammatory Response; Injectable; Interleukin-1; Interleukin-6; Knockout Mice; Lead; Legal patent; Leukocytes; Libraries; Liquid substance; Longevity; Lung; Marketing; Mediating; Metabolic; Modeling; Monomeric GTP-Binding Proteins; Mus; NF-kappa B; Natural regeneration; Nature; Non-Steroidal Anti-Inflammatory Agents; Pain; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Population; Positioning Attribute; Production; Purine Antagonist; Pyrimidine; Regulation; Rheumatoid Arthritis; Risk; Rodent; Rodent Model; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solubility; Specificity; Stress; Symptoms; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Thermodynamics; Tissues; Toxicology; Tuberculosis; United States; Universities; Utah; Vascular Endothelium; Vascular Permeabilities; Viral hepatitis; Work; base; combat; cytokine; disability; drug development; efficacy testing; falls; high throughput screening; improved; in vivo; inhibitor/antagonist; joint destruction; mouse model; novel; preclinical study; prevent; programs; public health relevance; response; rituximab; screening; small molecule; tool; tumor; vascular inflammation

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States and up to 1.5% of the population worldwide. In its progressive form the disease has debilitating effects including painful inflammation and destruction of the joints. This affliction leads to considerable lost work and disability. A hallmark of the RA inflammatory response is vascular instability. The vascular endothelium is continuously balancing the requirement to maintain a stable network with a capacity to regenerate. It is continuously challenged by destabilizing factors in response to inflammatory stress. An increase in vascular permeability in RA leads to infiltration of the synovial endothelium by leukocytes. Indeed, this may be a critical first step in initiation of RA, as well a its progression. We have shown that inhibition of a non-canonical ARNO/Arf6 pathway, independent of the canonical NF-kB pathway and immune system regulation is involved in maintaining vascular stability and provides consistent therapeutic benefit in a mouse model of RA. Current therapeutics for RA fall into a number of categories: cytokine inhibitors, B cell and T cel depleting or blocking agents, inhibitors of purine and pyrimidine synthesis, NSAIDs, and corticosteroids. While their direct mechanisms of action are varied, the central strategy of these therapies is to dampen the immune response via inhibition of the NF-kB pathway. The dominant market players are costly anti-TNF injectable therapies that carry a considerable risk of increased infection. The goal of this project is to identify clinically and commercially viable structural classes of ARNO/Arf6 small molecule inhibitors that may be effective at preventing the advancement of RA. At completion of this Phase I grant, we will have identified a series of structural classes and hit compounds that reduce endothelial permeability. In Phase II our efforts will focus on optimizing hit compounds for solubility, permeability, metabolic stability, and specificity, while minimizing potential safety concerns. The resulting lead compounds must be novel chemical entities that can be patent protected. Following this optimization step, lead compounds will be tested in in vivo RA models, and their pharmacokinetic, ADME, and safety profiles will be established. By the end of Phase II, we will have a set of prioritized leads and will be well-positioned to begin IND-enabling preclinical studies.

描述(由申请人提供)：类风湿性关节炎(RA)影响着美国约130万成年人，占全球人口的1.5%。在进展期，这种疾病会产生衰弱的影响，包括疼痛、炎症和关节的破坏。这种痛苦导致了相当大的失业和残疾。 RA炎症反应的一个特征是血管不稳定。血管内皮细胞不断地平衡着维持稳定的网络和再生能力的需求。它不断受到不稳定因素的挑战，以应对炎症应激。类风湿关节炎患者血管通透性增加导致滑膜内皮细胞被白细胞渗入。事实上，这可能是启动类风湿关节炎的关键的第一步，也是类风湿关节炎的进展。我们已经证明，抑制非典型的Arno/Arf6途径，独立于典型的NF-kB途径和免疫系统调节，参与维持血管稳定，并在小鼠RA模型中提供一致的治疗益处。 目前治疗类风湿性关节炎的药物分为几类：细胞因子抑制剂、B细胞和T细胞耗竭或阻滞剂、嘌呤和嘧啶合成抑制剂、非甾体抗炎药和皮质类固醇。虽然它们的直接作用机制各不相同，但这些疗法的中心策略是通过抑制核因子-kB途径来抑制免疫反应。占主导地位的市场参与者是昂贵的抗肿瘤坏死因子注射疗法，这些疗法具有相当大的感染增加风险。 该项目的目标是确定在临床和商业上可行的Arno/Arf6小分子抑制剂的结构类别，这些结构类别可能有效地防止RA的进展。在完成这项第一阶段拨款后，我们将确定一系列结构类别和 能降低血管内皮细胞通透性的化合物。在第二阶段，我们的努力将集中在优化HIT化合物的溶解性、渗透性、代谢稳定性和特异性，同时将潜在的安全问题降至最低。由此产生的先导化合物必须是可以受专利保护的新型化学实体。在这一优化步骤之后，先导化合物将在活体RA模型中进行测试，并将建立它们的药代动力学、ADME和安全性概况。到第二阶段结束时，我们将有一系列优先考虑的线索，并将处于有利地位，开始支持IND的临床前研究。