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: 8546227
• 负责人: KAREN G. ANTHONY
• 金额: $ 43.69万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546227
• 关键词: Address; Affinity; Animal Model; Apoptosis; Area; Arthritis; Back; Binding; Biological; Biological Assay; Cellular Assay; Characteristics; Chemicals; Complex; Coupled; Data; Development; Disease; Enzymes; Evaluation; Event; Future; Goals; Immigration; Inflammation; Inflammatory; Inflammatory Response; Joints; Lead; Mammalian Cell; Mass Spectrum Analysis; Mediating; Migration Inhibitory Factor; Modeling; Mus; Pathology; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Production; Qualifying; Rheumatoid Arthritis; Series; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; Surface Plasmon Resonance; Therapeutic; TimeLine; Treatment Efficacy; Vision; Work; analog; cytokine; cytotoxic; cytotoxicity; drug discovery; effective therapy; efficacy evaluation; functional group; immunopathology; improved; inhibitor/antagonist; interest; joint destruction; mouse model; novel; pharmacophore; phenylpyruvate tautomerase; pre-clinical; preclinical evaluation; process optimization; prophylactic; receptor; small molecule; therapeutic target

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.

描述（由申请人提供）：本项目的长期产品目标是一种治疗类风湿性关节炎（RA）的小分子治疗药物，通过减少促炎细胞因子巨噬细胞移动抑制因子（MIF）引发的炎症反应发挥作用。由于MIF是炎症级联反应的上游调节剂，因此靶向MIF活性的小分子治疗剂有望为RA提供有效治疗，目前仅在美国就有400万人患有RA，并且没有治愈性疗法。为此，在SBIR项目的第一阶段，我们筛选了20万种MIF抑制剂化合物，并鉴定了许多小分子，这些小分子阻断了与RA免疫病理学相关的MIF驱动的细胞活化途径。对于该提案，我们选择了两种结构独特且具有以前与MIF抑制活性无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。在这个项目的延续中，我们建议通过获得MIF抑制剂共晶体结构来阐明其精确的作用机制。此外，使用由结构数据指导的药物化学，我们建议获得结构-活性关系并修改化合物以改善其MIF抑制活性，以获得在RA小鼠模型中有效的分子。所有这些努力预期产生适合于进一步开发用于RA的小分子治疗剂的先导化合物。