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.

项目摘要/摘要 贫血是常见疾病，与许多疾病有关，包括终阶段 肾脏疾病。红细胞素蛋白（EPO）的重组版本，调节红色的钥匙扣 血细胞肿块已成为这种情况的主要治疗方法。父母的必要 但是，管理已促使人们寻找增加红色细胞的替代方法 大量的。在这方面，红细胞增多症患者的一部分港口丧失功能突变 丙酰羟化酶域蛋白2（PHD2，也称为EGLN1）基因，从而鉴定 编码蛋白质PHD2作为增加红细胞质量的有吸引力的靶标。 PHD2是关键 下调低氧诱导因子-（HIF-）的酶，进而激活EPO 基因。确实，其他地方正在努力抑制PHD2的主动部位 治疗贫血的方法。但是，PHD2的催化域与其他 蛋白质，因此警告努力更具体地抑制PHD2。 phd2在藏有一个锌指域，就像其催化域一样 有效下调HIF-必不可少的。在演示申请中，我们提出了目标 该锌指的是增加HIF-并增加红细胞质量。在初步 研究，我们对可以抑制相互作用的化合物进行了α筛选 在PHD2及其配体的锌指中 促进HIF-羟基化的途径。我们已经确定了可以破坏这一点的化合物 相互作用。我们提出以下特定目标。首先，我们希望确定结构活动 关系的目的是改善抑制作用。第二，我们试图获得可接受的ADME/PK 至少一种或两种化合物的药物值。第三，我们建议将此化合物注入 一种新型的敲蛋白小鼠系，其中PHD2基因具有人源化的锌指 与体外研究确定的化合物的相互作用。根据，此申请涉及 将Fox Chase化学的药物化学专家汇集在一起​​的合作伙伴关系 多样性中心，具有大学主要研究人员实验室的经验 宾夕法尼亚州检查HIF途径。该项目的长期目标是确定 可以在更详细的指定研究中评估的临床前候选者。这样的 候选人将成为治疗贫血的有前途的药物。