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对类风湿关节炎患者（RA）的一种小分子治疗，该治疗方法将通过减少巨噬细胞迁移抑制因子（MIF）触发的炎症反应来起作用。 RA在美国最多可容纳400万人，这种疾病的医疗保健和间接费用很大。尽管有几种治疗方法，但它们都没有100％有效，其中一些人随着时间的流逝而失去有效性。 RA的确切病因尚未完全理解，但是该疾病是由关节滑膜炎症和血管生成引起的，导致关节破坏和侵入性Pannus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活性的化合物可能会在该疾病中提供益处。在一项试点研究中，使用MIF的次脉（非生理）互变异酶活性的高通量筛选测定法被用来识别9次命中。这些命中中的三个还抑制了MIF与其同源受体的结合，这对于MIF的生物活性至关重要。该屏幕将扩展到较大的库，该文库可能会产生其他新型的MIF互变异酶活性的小分子抑制剂，这将成为该阶段I项目的其他候选者。在此I阶段项目中，将采用一组MIF活性的生化和生物学测定，以进一步表征和基于MIF的抑制：受体结合和随后的细胞激活。这些包括对MIF触发的ERK1/2磷酸化的测定，抑制p53诱导的凋亡以及炎症细胞因子和基质降解酶的分泌，所有这些酶都会导致RA关节中pannus的炎症和阳性产物。该阶段I项目的最终产物将是抑制MIF驱动的细胞激活途径的一系列流行，这些途径有助于RA的免疫病理学。这些热门歌曲将是随后的II期项目的候选者，其中包括药物和计算化学努力，以产生具有更高效力和更有利的药物样特性的潜在客户，以及使用RA动物模型的体内研究。成功完成II期目标后，我们将与许多大型，成熟的制药公司之一合作开始临床和临床开发工作，他们分享我们对新治疗剂的愿景，这些愿景将减少RA中MIF诱导的免疫病理学。 公共卫生相关性：该项目的目的是识别和开发用于治疗类风湿关节炎（RA）的小分子治疗化合物，这种疾病遭受了美国高达400万人的疾病。这些化合物将通过抑制由细胞因子巨噬细胞迁移抑制因子（MIF）引起的RA炎症成分的能力来识别。由于MIF在RA的炎症级联反应中行动，因此对该活性的抑制作用将解决许多最终导致关节破坏的下游效应途径。