Therapeutic Inhibition of MIF in Rheumatoid Arthritis

描述（由申请人提供）：本项目的长期目标是一种对类风湿性关节炎（RA）患者有益的小分子治疗药物，其将通过减少巨噬细胞迁移抑制因子（MIF）引发的炎症反应发挥作用。在美国，RA折磨着多达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，但没有一种是100%有效的，其中一些随着时间的推移而失去效果。RA的确切病因尚不完全清楚，但已确定该疾病是由关节滑膜衬里中的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活性的化合物可以在这种疾病中提供益处。在一项初步研究中，利用MIF的残留（非生理性）互变异构酶活性的高通量筛选试验被用于鉴定9个命中。这些命中中的三个还抑制MIF与其同源受体的结合，这是MIF生物活性中的关键步骤。该筛选将扩展到更大的文库，这可能产生额外的MIF互变异构酶活性的新型小分子抑制剂，其将成为该I期项目的额外候选物。在该I期项目中，将采用一组MIF活性的生物化学和生物学测定来进一步表征和排序基于MIF抑制的命中：受体结合和随后的细胞活化。这些包括MIF触发的ERK 1/2磷酸化、p53诱导的细胞凋亡的抑制以及炎性细胞因子和基质降解酶的分泌的测定，所有这些都有助于RA关节中血管翳的炎症和生长。这个I期项目的最终产品将是一组抑制MIF驱动的细胞激活途径的命中，有助于RA的免疫病理学。这些命中将是随后的第二阶段项目的候选人，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样特性的线索，以及使用RA动物模型的体内研究。在成功完成II期目标后，我们将与众多大型、成熟的制药公司之一合作，开始临床前和临床开发工作，这些公司与我们分享了减少类风湿关节炎中MIF诱导的免疫病理学的新疗法的愿景。 公共卫生相关性：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，RA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迁移抑制因子（MIF）引起的RA的炎症组分的能力来鉴定。由于MIF在RA的炎症级联反应中起上游作用，因此抑制这种活性将解决许多最终导致关节破坏的下游效应途径。

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.