Allosteric MIF Inhibitors for Rheumatoid Arthritis Therapy

用于类风湿关节炎治疗的变构 MIF 抑制剂

• 批准号: 9381096
• 负责人: KAREN G. ANTHONY
• 金额: $ 0.61万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381096
• 关键词: Affect; Affinity; Animal Model; Area; Binding; Binding Sites; Bioavailable; Biological; Biological Assay; Biological Availability; Calorimetry; Catalytic Domain; Cellular Assay; Chemicals; Collagen-Induced Arthritis; Complex; Crystallization; Crystallography; Data; Development; Disease; Disease Progression; Disease model; Dopachrome isomerase; Drug Design; Drug Kinetics; Enzymes; Future; Genetic; Goals; Homologous Gene; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; LIF gene; Lead; Mediating; Mediator of activation protein; Migration Inhibitory Factor; Modeling; Mus; Oral; Pathology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Process; Property; Public Health; Research Project Grants; Rheumatoid Arthritis; Safety; Series; Structure; Structure-Activity Relationship; Surface; Surface Plasmon Resonance; Testing; Therapeutic; TimeLine; Toxicology; Vision; Work; analog; arthritis therapy; arthropathies; base; biophysical techniques; course development; cytokine; efficacy evaluation; efficacy testing; functional group; improved; in vivo; inhibitor/antagonist; interest; joint destruction; mouse model; novel; novel therapeutics; phenylpyruvate tautomerase; preclinical development; preclinical evaluation; process optimization; receptor binding; small molecule; structural biology; therapeutic development

Abstract The long-term product goal of this project is a small molecule rheumatoid arthritis (RA) therapeutic which acts by reducing the inflammatory response triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). The therapeutic benefit of MIF inhibition in RA disease models has been well established by small molecules that bind to a catalytic site of the MIF trimer that mediates the cytokine's vestigial (non-physiological) tautomerase activity. However, allosteric binding of inhibitors in regions outside the tautomerase pocket to date remains ill investigated as a therapeutic approach to blocking MIF's cytokine activities. Our research project focuses on therapeutic development of such allosteric MIF inhibitors. Through structure-based drug design, we have obtained a unique class of compounds, which as revealed by crystallography, bind on the surface of the MIF trimer directly above the tautomerase pocket and overlap the MIF's CD74 receptor binding site that is central to MIF function. In vitro tautomerase, CD74-binding, and bioassays revealed that these allosteric inhibitors not only blocked the activities of MIF, but also those of D- dopachrome tautomerase (D-DT or MIF-2), the MIF homolog in humans whose simultaneous inhibition in MIF- related diseases appears necessary for therapeutic benefit. These preliminary results support further development of this class of allosteric MIF inhibitors as leads for MIF-directed RA therapy. Our hypothesis is that this class of MIF/D-DT allosteric inhibitors will reduce the inflammatory responses triggered by these cytokines, and therefore will prove beneficial in treating RA. In this project, building from our extensive preliminary data, we propose to use medicinal chemistry guided by structural studies to modify the inhibitors for improved MIF and D-DT-inhibition in an effort to obtain molecules that are efficacious in the RA mouse model. The work proposed in the three specific aims of our project focuses on (1) modifying the inhibitors to obtain a structure-activity relationship, (2) introducing functional groups to gradually improve their target binding and potency in MIF-mediated tautomerase and bioassays and (3) evaluating efficacy in the mouse model of collagen-induced arthritis. These efforts are expected to yield a lead compound suitable for further development towards an orally bio-available small molecule MIF-directed therapeutic for RA.

抽象的 该项目的长期产品目标是一种小分子类风湿关节炎（RA）治疗，其作用 通过减少促炎性细胞因子巨噬细胞迁移触发的炎症反应 抑制因子（MIF）。 MIF抑制在RA疾病模型中的治疗益处很好 由小分子与介导细胞因子的MIF三聚体的催化位点结合的小分子建立 遗传（非生理）互变异酶活性。但是，抑制剂在外部地区的变构结合 截至迄今为止的互变异酶袋仍被调查为阻断MIF细胞因子的治疗方法 活动。我们的研究项目着重于这种变构MIF抑制剂的治疗性开发。 通过基于结构的药物设计，我们获得了一类独特的化合物，如 晶体学，结合在互变异酶袋上方的MIF三聚体的表面上，并重叠 MIF的CD74受体结合位点是MIF功能的中心。体外互变异酶，CD74结合和 生物测定表明，这些变构抑制剂不仅阻止了MIF的活性，而且还阻止了D-的活性 多巴罗姆互变异酶（DT或MIF-2），人类的MIF同源物，其同时抑制MIF- 相关疾病似乎是治疗益处所必需的。这些初步结果进一步支持 开发这类变构MIF抑制剂作为MIF定向RA疗法的铅。我们的假设是 这类MIF/D-DT变构抑制剂将减少由 这些细胞因子，因此将证明有益于治疗RA。在这个项目中，从我们的 广泛的初步数据，我们建议使用以结构研究为指导的药物化学反应 修改抑制剂以改善MIF和DT抑制作用，以获取分子 在RA鼠标模型中有效。我们项目的三个特定目标中提出的工作重点 （1）修改抑制剂以获得结构活性关系，（2）将功能组引入 逐渐改善MIF介导的互变异酶和生物测定的目标结合和效力，以及（3） 评估胶原蛋白诱导关节炎小鼠模型中的功效。这些努力有望产生领先 化合物适用于向口服生物利用的小分子MIF定向的进一步开发 RA的治疗性。