Therapeutic Inhibition of MIF in Rheumatoid Arthritis

描述（由申请人提供）：该项目的长期产品目标是治疗类风湿性关节炎（RA）的小分子药物，其作用是减少由促炎细胞因子巨噬细胞迁移抑制因子（MIF）引发的炎症反应。由于MIF是炎症级联的上游调节因子，靶向MIF活性的小分子疗法有望为类风湿性关节炎提供有效治疗，目前仅在美国就有400万人患有这种疾病，而且尚无治愈性治疗方法。为此，在SBIR项目的I期中，我们筛选了200,000种MIF抑制剂化合物，并确定了一些小分子，这些小分子可以阻断与RA免疫病理相关的MIF驱动的细胞激活途径。为此，我们选择了两种结构独特且具有先前未与MIF抑制活性相关的官能团的抑制剂。它们似乎通过不同的机制与MIF相互作用，并且它们对哺乳动物细胞没有细胞毒性。在这个项目的继续，我们建议通过获得mif抑制剂的共晶结构来阐明它们的确切作用机制。进一步，在结构数据的指导下，利用药物化学，我们建议获得结构-活性关系，并对化合物进行修饰以提高其mif抑制活性，以获得在RA小鼠模型中有效的分子。所有这些努力都有望产生一种先导化合物，适合进一步开发小分子治疗类风湿性关节炎。

DESCRIPTION (provided by applicant): The long-term product goal of this project is a small molecule therapeutic to treat rheumatoid arthritis (RA), which acts by reducing the inflammatory response triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). Since MIF is an upstream regulator of the inflammatory cascade, small molecule therapeutics targeting MIF activity are expected to provide effective treatment for RA, which currently afflicts 4 million people in the US alone and for which there is no curative therapy. To this end, in Phase I of this SBIR project, we screened 200,000 compounds for MIF inhibitors and identified a number of small molecules that block MIF-driven cellular activation pathways that are associated with the immunopathology of RA. For this proposal we selected two inhibitors that are structurally unique and possess functional groups that have not been previously associated with MIF inhibitory activity. They appear to interact with MIF by distinct mechanisms, and they are not cytotoxic to mammalian cells. In the continuation of this project, we propose to elucidate their precise mechanisms of action by obtaining MIF-inhibitor co-crystal structures. Further, using medicinal chemistry guided by structural data, we propose to obtain structure-activity relationships and modify the compounds to improve their MIF-inhibitory activities in an effort to obtain molecules that are efficacious in the RA mouse model. All of these efforts are expected to yield a lead compound suitable for further development towards a small molecule therapeutic for RA.