INHIBITORS OF THE PHD2 ZINC FINGER TO TREAT ANEMIA

PHD2 锌指抑制剂治疗贫血

• 批准号: 9345190
• 负责人: Jay Edward Wrobel
• 金额: $ 30万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345190
• 关键词: Active Sites; Address; Adverse effects; Anemia; Applications Grants; Binding; Binding Proteins; Biological Assay; Catalytic Domain; Cell Count; Cell Proliferation; Cells; Chemicals; Client; DNA; Data; Development; Dioxygenases; Disease; Doctor of Philosophy; Down-Regulation; End stage renal failure; Enzymes; Erythrocytes; Evaluation; Family; Foxes; Gene Targeting; Genes; Goals; HIV Infections; Half-Life; Hearing Impaired Persons; Heat-Shock Proteins 90; Hematocrit procedure; Hemoglobin; Histones; Hormones; Hydroxylation; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Injectable; Intellectual Property; Knock-in Mouse; Laboratories; Lead; Libraries; Ligands; Measures; Metabolic; Methods; Microsomes; Modification; Molecular; Mus; Myelogenous; Oral; Oxygen; Pathway interactions; Pennsylvania; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma Proteins; Play; Positioning Attribute; Preparation; Principal Investigator; Procollagen-Proline Dioxygenase; Production; Property; Protein Isoforms; Proteins; RNA; Recombinant Erythropoietin; Recombinants; Recruitment Activity; Red Cell Mass result; Risk; Role; Serum; Site; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Solubility; Specificity; Structure-Activity Relationship; Technology; Tertiary Protein Structure; Testing; Text; Universities; Validation; Zinc Fingers; alpha ketoglutarate; analog; aqueous; base; counterscreen; demethylation; design; drug discovery; experience; high throughput screening; improved; in vitro Assay; in vivo; inhibitor/antagonist; lipophilicity; loss of function mutation; member; mouse model; neuron apoptosis; neurotoxicity; novel; novel therapeutic intervention; parenteral administration; patient subsets; pre-clinical; programs; prototype; sensor; small molecule

PROJECT SUMMARY/ABSTRACT Anemia is common disease and is associated with many conditions, including end-stage renal disease. Recombinant versions of Erythropoeitin (EPO), the key hormone that regulates red blood cell mass, have been a mainstay of treatment for this condition. The necessity of parenteral administration, however, has prompted the search for alternative methods for increasing red cell mass. In this regard, a subset of patients with erythrocytosis harbor loss of function mutations in the Prolyl Hydroxylase Domain protein 2 (PHD2, also known as EGLN1) gene, thereby identifying the encoding protein, PHD2, as an attractive target to increase red cell mass. PHD2 is the key enzyme that downregulates Hypoxia Inducible Factor- (HIF-), which, in turn, activates the EPO gene. Indeed there are efforts underway elsewhere to inhibit the active site of PHD2 as an approach to treating anemia. However, the catalytic domain of PHD2 is homologous to other proteins, thereby warranting efforts to more specifically inhibit PHD2. PHD2 is distinctive in harboring a zinc finger domain that, like its catalytic domain, is essential for efficient downregulation of HIF-. In the present application, we propose targeting this zinc finger in order to increase HIF- and thereby increase red cell mass. In preliminary studies, we have conducted an Alpha Screen for compounds that can inhibit the interaction between the zinc finger of PHD2 and its ligand, which serves to recruit PHD2 to the HSP90 pathway to facilitate HIF- hydroxylation. We have identified compounds that can disrupt this interaction. We propose the following Specific Aims. First, we wish to identify structure activity relationships with the aim of improving inhibition. Second, we seek to attain acceptable ADME/PK drug values for at least one or two compounds. Third, we propose injecting this compound(s) into a novel knockin mouse line in which the Phd2 gene has a humanized zinc finger so as to allow interaction with compounds identified by the in vitro studies. Accordingly, this application involves a partnership that brings together the medicinal chemistry expertise of the Fox Chase Chemical Diversity Center with the experience of the Principal Investigator’s laboratory at the University of Pennsylvania in examining the HIF pathway. The long term goal of this project will be to identify a preclinical candidate that can be evaluated in more detailed IND-directed studies. Such a candidate will be promising agent for the treatment of anemia.

项目总结/摘要 贫血是一种常见病，与多种疾病有关，包括终末期贫血。 肾脏疾病重组版本的促红细胞生成素（EPO），调节红色的关键激素 血细胞质量一直是治疗这种疾病的主要手段。胃肠外的必要性 然而，政府已经促进了对增加红细胞数量的替代方法的研究。 马萨诸塞州在这方面，红细胞增多症患者的一个亚组在红细胞功能缺失突变中， 脯氨酰羟化酶结构域蛋白2（PHD 2，也称为EGLN 1）基因，从而鉴定 编码蛋白PHD2作为增加红细胞质量的有吸引力的靶点。PHD2是关键 一种下调缺氧诱导因子-β（HIF-β）的酶，而HIF-β反过来又激活EPO 基因事实上，其他地方正在努力抑制PHD 2的活性位点作为一种抑制剂。 治疗贫血的方法然而，PHD2的催化结构域与其他蛋白同源， 蛋白质，从而阻止更特异性地抑制PHD2的努力。 PHD 2的独特之处在于含有锌指结构域，该锌指结构域与其催化结构域一样， 对HIF-1 α的有效下调至关重要。在本申请中，我们提出靶向 这种锌指是为了增加HIF-1 α，从而增加红细胞质量。初步 研究中，我们已经进行了一个阿尔法筛选的化合物，可以抑制相互作用 PHD 2的锌指与其配体之间，其用于将PHD 2募集到HSP 90 促进HIF-1 α羟基化的途径。我们已经鉴定出了可以破坏这一过程的化合物 互动我们提出以下具体目标。首先，我们希望识别结构活动 以改善抑制为目的。第二，我们寻求达到可接受的ADME/PK 至少一种或两种化合物的药物值。第三，我们建议将这种化合物注入 一种新的敲入小鼠系，其中Phd2基因具有人源化锌指， 与通过体外研究鉴定的化合物的相互作用。因此，本申请涉及 合作伙伴关系，汇集了福克斯大通化学公司的药物化学专业知识， 多样性中心，具有在密歇根大学首席研究员实验室的经验。 宾夕法尼亚州在研究HIF途径。该项目的长期目标是确定一个 临床前候选药物，可在更详细的IND指导研究中进行评价。这样的 候选物将是治疗贫血的有希望的药剂。