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.

摘要 该项目的长期产品目标是一种小分子类风湿关节炎（RA）治疗剂， 通过减少由促炎细胞因子巨噬细胞迁移引发的炎症反应 抑制因子（MIF）。在RA疾病模型中，MIF抑制的治疗益处已经很好地被证实。 通过与MIF三聚体的催化位点结合的小分子建立，所述MIF三聚体介导细胞因子的 残留（非生理学）互变异构酶活性。然而，抑制剂在外部区域的变构结合， 迄今为止，互变异构酶口袋作为阻断MIF的细胞因子的治疗方法仍然没有得到充分的研究 活动我们的研究项目集中在这种变构MIF抑制剂的治疗开发。 通过基于结构的药物设计，我们已经获得了一类独特的化合物， 在晶体学上，结合在直接位于互变异构酶口袋上方的MIF三聚体的表面上，并与互变异构酶口袋重叠。 MIF的CD 74受体结合位点，对MIF功能至关重要。体外互变异构酶、CD 74结合和 生物测定表明，这些变构抑制剂不仅阻断了MIF的活性，而且也阻断了D- 多巴色素互变异构酶（D-DT或MIF-2），人类中的MIF同系物，其同时抑制MIF-2， 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了 开发这类变构MIF抑制剂作为MIF导向的RA治疗的先导。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，并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，我们建议使用药物化学指导的结构研究， 修饰抑制剂以改善MIF和D-DT抑制，以获得 在RA小鼠模型中有效。我们项目的三个具体目标中提出的工作重点是 (1)对抑制剂进行修饰，获得构效关系;（2）引入官能团， 在MIF介导的互变异构酶和生物测定中逐渐改善其靶结合和效力，以及（3） 评价在胶原诱导的关节炎小鼠模型中的功效。这些努力有望取得领先 适合于进一步开发口服生物可利用的小分子MIF导向的化合物 治疗RA。