Therapeutic Inhibition of MIF in Rheumatoid Arthritis

MIF 在类风湿性关节炎中的治疗抑制作用

• 批准号: 7670901
• 负责人: KAREN G. ANTHONY
• 金额: $ 23.97万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670901
• 关键词: Address; Angiogenic Factor; Animal Model; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Catalytic Domain; Cell Surface Receptors; Cell physiology; Clinical; Collaborations; Development; Disease; Effectiveness; Enzymes; Etiology; Event; Facilities and Administrative Costs; Goals; Healthcare; Inflammation; Inflammatory; Inflammatory Response; Joints; Letters; Libraries; Ligand Binding; Matrix Metalloproteinases; Migration Inhibitory Factor; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphorylation; Phosphorylation Inhibition; Physiological; Pilot Projects; Production; Property; Receptor Inhibition; Rheumatoid Arthritis; Signal Transduction; Testing; Therapeutic; Time; TimeLine; Tissues; Vision; angiogenesis; base; computational chemistry; cytokine; cytotoxicity; high throughput screening; immunopathology; in vivo; inhibitor/antagonist; joint destruction; novel; novel therapeutics; phenylpyruvate tautomerase; pre-clinical; preclinical study; programs; public health relevance; receptor; receptor binding; response; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): The long-term goal of this project is a small molecule therapeutic of benefit to patients with rheumatoid arthritis (RA), which will act by reducing the inflammatory response triggered by macrophage migration inhibitory factor (MIF). RA afflicts up to 4 million people in the U.S., and the healthcare and indirect costs of this disease are significant. While several treatments are available, none of them are 100% effective and some of them lose effectiveness with time. The precise etiology of RA is not completely understood, but it is well-established that the disease is caused by inflammation and angiogenesis in the synovial lining of the joints, leading to joint destruction and the outgrowth of the invasive pannus. MIF has been implicated in the immunopathology of RA in clinical and preclinical studies, thus compounds which inhibit MIF activity may provide benefit in this disease. In a pilot study, a high-throughput screening assay that takes advantage of the vestigial (non-physiologic) tautomerase activity of MIF was used to identify nine hits. Three of those hits also inhibit binding of MIF to its cognate receptor, a step which is critical in the biological activity of MIF. This screen will be expanded to a larger library, which is likely to yield additional novel small molecule inhibitors of MIF tautomerase activity that will become additional candidates for this Phase I project. In this Phase I project, a panel of biochemical and biological assays of MIF activity will be employed to further characterize and rank order hits based on inhibition of MIF:receptor binding and subsequent cellular activation. These include assays for MIF-triggered ERK1/2 phosphorylation, inhibition of p53-induced apoptosis, and secretion of inflammatory cytokines and matrix- degrading enzymes, all of which contribute to the inflammation and outgrowth of pannus in RA joints. The final product of this Phase I project will be a panel of hits that inhibit MIF-driven cellular activation pathways that contribute to the immunopathology of RA. These hits will be candidates for a subsequent Phase II project, which will include medicinal and computational chemistry efforts to produce leads with higher potency and more favorable drug-like properties, as well as in vivo studies using an animal model of RA. Upon successful completion of Phase II objectives, we will commence pre-clinical and clinical development efforts in partnership with one of a number of large, well-established pharmaceutical firms who share our vision for new therapeutics that will reduce MIF-induced immunopathology in RA. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify and develop small molecule therapeutic compounds for the treatment of rheumatoid arthritis (RA), a disease which afflicts up to 4 million people in the US. These compounds will be identified by their ability to inhibit the inflammatory component of RA that is caused by the cytokine macrophage migration inhibitory factor (MIF). Since MIF acts upstream in the inflammatory cascade in RA, inhibition of this activity will address many of the downstream effector pathways that are ultimately responsible for joint destruction.

描述(申请人提供)：该项目的长期目标是一种对类风湿性关节炎(RA)患者有益的小分子疗法，它将通过减少巨噬细胞移动抑制因子(MIF)引发的炎症反应来发挥作用。在美国，RA困扰着多达400万人，这种疾病的医疗保健和间接成本是巨大的。虽然有几种治疗方法可用，但没有一种是100%有效的，其中一些随着时间的推移而失效。RA的确切病因尚不完全清楚，但众所周知，该病是由关节滑膜衬里的炎症和血管生成引起的，导致关节破坏和侵袭性血管疙瘩的生长。在临床和临床前研究中，MIF参与了RA的免疫病理过程，因此，抑制MIF活性的化合物可能对RA有好处。在一项初步研究中，利用MIF的残留(非生理性)互变构酶活性的高通量筛选试验被用来识别9个命中。其中三个HIT还抑制MIF与其同源受体的结合，这一步骤在MIF的生物学活性中至关重要。这一筛选将扩大到更大的文库，这可能会产生更多的新型MIF互换擦除酶活性的小分子抑制剂，这将成为这个第一阶段项目的额外候选药物。在这个第一阶段项目中，将使用一组MIF活性的生化和生物学分析来进一步表征和排序基于对MIF的抑制的HITS：受体结合和随后的细胞激活。这些包括MIF触发的ERK1/2磷酸化的检测，抑制P53诱导的细胞凋亡，以及炎性细胞因子和基质降解酶的分泌，所有这些都有助于RA关节血管疙瘩的炎症和生长。这一第一阶段项目的最终产品将是一组HIT，它可以抑制MIF驱动的细胞激活途径，这些途径有助于RA的免疫病理。这些成功将是后续第二阶段项目的候选项目，该项目将包括药物和计算化学努力，以生产具有更高效力和更有利的类药物特性的先导，以及使用类风湿关节炎动物模型进行体内研究。在成功完成第二阶段目标后，我们将与许多大型、久负盛名的制药公司之一合作，开始临床前和临床开发工作，这些公司分享了我们对减少MIF诱导的RA免疫病理的新疗法的愿景。 公共卫生相关性：该项目的目标是确定和开发用于治疗类风湿性关节炎(RA)的小分子治疗化合物，类风湿性关节炎是一种在美国困扰多达400万人的疾病。这些化合物将通过它们抑制由细胞因子巨噬细胞移动抑制因子(MIF)引起的RA炎症成分的能力来识别。由于MIF在RA的炎症级联反应中上游起作用，抑制这一活性将解决许多最终导致关节破坏的下游效应通路。