Therapeutic Inhibition of MIF in Rheumatoid Arthritis

MIF 在类风湿性关节炎中的治疗抑制作用

基本信息

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
项目类别：
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

项目摘要

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治疗类风湿性关节炎（RA）的小分子疗法，其通过减少促炎细胞因子巨噬细胞迁移抑制因子（MIF）引发的炎症反应来发挥作用。由于 MIF 是炎症级联的上游调节因子，因此针对 MIF 活性的小分子疗法有望为 RA 提供有效的治疗，目前仅在美国就有 400 万人患有 RA，而且尚无治愈方法。为此，在该 SBIR 项目的第一阶段，我们筛选了 200,000 种 MIF 抑制剂化合物，并鉴定了许多阻断 MIF 驱动的与 RA 免疫病理学相关的细胞激活途径的小分子。对于该提案，我们选择了两种结构独特的抑制剂，它们具有以前未与 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。在该项目的后续工作中，我们建议通过获得 MIF 抑制剂共晶结构来阐明其精确的作用机制。此外，利用结构数据指导的药物化学，我们建议获得结构-活性关系并修饰化合物以提高其 MIF 抑制活性，以获得在 RA 小鼠模型中有效的分子。所有这些努力预计将产生适合进一步开发 RA 小分子治疗剂的先导化合物。公共健康相关性：该项目的目标是推动一种有前景的小分子化合物开发成治疗类风湿性关节炎 (RA) 的新药，这种疾病困扰着美国多达 400 万人。该化合物似乎可以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。由于 MIF 在 RA 炎症级联反应的上游发挥作用，抑制这种活性将解决许多最终导致关节破坏的下游效应通路。