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（由申请人提供）：该项目的长期目标是开发一种对类风湿性关节炎（RA）患者有益的小分子治疗药物，通过减少巨噬细胞迁移抑制因子（MIF）引发的炎症反应来发挥作用。在美国，类风湿性关节炎（RA）困扰着多达 400 万人，这种疾病造成的医疗保健和间接成本巨大。虽然有多种治疗方法可供选择，但没有一种方法是 100% 有效的，而且有些方法会随着时间的推移而失效。 RA 的确切病因尚不完全清楚，但已明确该疾病是由关节滑膜内层炎症和血管生成引起的，导致关节破坏和侵袭性血管翳的生长。在临床和临床前研究中，MIF 与 RA 的免疫病理学有关，因此抑制 MIF 活性的化合物可能对这种疾病有益。在一项初步研究中，利用 MIF 残留（非生理）互变异构酶活性的高通量筛选测定法来鉴定 9 个命中。其中三个命中还抑制 MIF 与其同源受体的结合，这一步骤对于 MIF 的生物活性至关重要。该筛选将扩展到更大的文库，这可能会产生更多新型 MIF 互变异构酶活性小分子抑制剂，这些抑制剂将成为该 I 期项目的其他候选药物。在这个第一阶段项目中，将采用一组 MIF 活性的生化和生物测定来根据 MIF：受体结合和随后的细胞激活的抑制来进一步表征和排序命中。这些包括对 MIF 触发的 ERK1/2 磷酸化、p53 诱导的细胞凋亡的抑制以及炎症细胞因子和基质降解酶的分泌进行测定，所有这些都会导致 RA 关节中的炎症和血管翳生长。该第一阶段项目的最终产品将是一组抑制 MIF 驱动的细胞激活途径的热门产品，这些途径有助于 RA 的免疫病理学。这些成果将成为后续二期项目的候选者，该项目将包括药物和计算化学工作，以产生具有更高效力和更有利的药物特性的先导化合物，以及使用 RA 动物模型进行体内研究。成功完成 II 期目标后，我们将与多家知名大型制药公司之一合作，开始临床前和临床开发工作，这些公司与我们对新疗法的愿景相同，这些新疗法将减少 RA 中 MIF 诱导的免疫病理学。 公共健康相关性：该项目的目标是识别和开发用于治疗类风湿性关节炎 (RA) 的小分子治疗化合物，这种疾病困扰着美国多达 400 万人。这些化合物将通过其抑制由细胞因子巨噬细胞迁移抑制因子 (MIF) 引起的 RA 炎症成分的能力来鉴定。由于 MIF 在 RA 炎症级联反应的上游发挥作用，抑制这种活性将解决许多最终导致关节破坏的下游效应通路。