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: 8252707
• 负责人: KAREN G. ANTHONY
• 金额: $ 55.19万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252707
• 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. PUBLIC HEALTH RELEVANCE: The goal of this project is to advance a promising small molecule compound towards development into a new drug for the treatment of rheumatoid arthritis (RA), a disease that afflicts up to 4 million people in the US. This compound appears 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）：该项目的长期产品目标是一种用于治疗类风湿关节炎（RA）的小分子治疗方法，该治疗方法是通过减少促炎性细胞因子巨噬细胞迁移抑制因子（MIF）触发的炎症反应的作用。由于MIF是炎症性级联反应的上游调节剂，因此针对MIF活性的小分子疗法有望为RA提供有效的治疗方法，RA目前仅在美国单独遭受400万人的折磨，并且没有治疗治疗。为此，在该SBIR项目的I期中，我们筛选了200,000种用于MIF抑制剂的化合物，并确定了许多与RA免疫病理学相关的MIF驱动的细胞活化途径的小分子。对于此提案，我们选择了两个在结构上是独一无二的抑制剂，并且具有以前与MIF抑制活性相关的官能团。它们似乎通过不同的机制与MIF相互作用，并且对哺乳动物细胞没有细胞毒性。在该项目的延续中，我们建议通过获得MIF抑制剂共结晶结构来阐明其精确的作用机制。此外，使用以结构数据为指导的药物化学，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。所有这些努力都预计将产生适合进一步发育的铅化合物，用于针对RA的小分子治疗。 公共卫生相关性：该项目的目的是将有希望的小分子化合物推向开发成为一种用于治疗类风湿关节炎（RA）的新药，这种疾病会折磨于美国多达400万人。该化合物似乎抑制了由细胞因子巨噬细胞迁移抑制因子（MIF）引起的RA的炎症成分。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。