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.

项目概要/摘要 贫血是常见疾病，与许多疾病有关，包括终末期 肾脏疾病。促红细胞生成素 (EPO) 的重组版本，这是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方法。肠外注射的必要性 然而，管理已促使人们寻找增加红细胞的替代方法 大量的。在这方面，一部分红细胞增多症患者存在功能缺失突变 脯氨酰羟化酶结构域蛋白 2 (PHD2，也称为 EGLN1) 基因，从而鉴定 编码蛋白 PHD2 是增加红细胞质量的一个有吸引力的靶标。 PHD2是关键 下调缺氧诱导因子-α (HIF-α) 的酶，进而激活 EPO 基因。事实上，其他地方正在努力抑制 PHD2 作为一种药物的活性位点。 治疗贫血的方法。然而，PHD2 的催化结构域与其他 蛋白，从而需要努力更特异性地抑制 PHD2。 PHD2 的独特之处在于含有锌指结构域，与其催化结构域一样， 对于有效下调 HIF-α 至关重要。在本申请中，我们建议瞄准 该锌指可以增加 HIF-α，从而增加红细胞质量。在初步 研究中，我们对能够抑制相互作用的化合物进行了 Alpha 筛选 PHD2 的锌指与其配体之间，用于将 PHD2 招募到 HSP90 促进 HIF-α 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。我们提出以下具体目标。首先，我们希望确定结构活动 关系，以改善抑制作用。其次，我们寻求获得可接受的 ADME/PK 至少一种或两种化合物的药物值。第三，我们建议将该化合物注射到 一种新型敲入小鼠品系，其中 Phd2 基因具有人源化锌指，从而允许 与体外研究确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 Fox Chase Chemical 的药物化学专业知识 多样性中心拥有英国大学首席研究员实验室的经验 宾夕法尼亚州正在检查 HIF 通路。该项目的长期目标是确定一个 可以在更详细的 IND 导向研究中进行评估的临床前候选药物。这样一个 候选药物将成为治疗贫血的有前途的药物。