INHIBITORS OF THE PHD2 ZINC FINGER TO TREAT ANEMIA

项目摘要/摘要 贫血是一种常见病，与多种疾病有关，包括终末期 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 血细胞团，一直是治疗这种疾病的主要手段。肠外营养的必要性 然而，政府已经促使人们寻找增加红细胞的替代方法 质量。在这一点上，一部分红细胞增多症患者存在功能突变。 Pro羟基酶结构域蛋白2(PHD2，也称为EGLN1)基因，从而识别 编码蛋白PHD2被认为是增加红细胞质量的有吸引力的靶点。PHD2是关键 下调缺氧诱导因子-(HIF-)的酶，进而激活促红细胞生成素 吉恩。事实上，其他地方也在努力抑制PHD2作为一种 治疗贫血的方法。然而，PHD2的催化结构域与其他 蛋白质，从而保证了更具体地抑制PHD2的努力。 PHD2的独特之处在于含有锌指结构域，与其催化结构域一样， 对于有效下调缺氧诱导因子-至关重要。在本申请中，我们建议将目标 这种锌指可以增加缺氧诱导因子-，从而增加红细胞质量。在预赛中 研究表明，我们已经对能够抑制这种相互作用的化合物进行了阿尔法筛选 在PHD2的锌指和其配体之间，用于将PHD2招募到HSP90 促进缺氧诱导因子-羟化的途径。我们已经确定了可以破坏这一过程的化合物 互动。我们提出了以下具体目标。首先，我们希望确定结构活动 与改善抑制的目标之间的关系。第二，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价值。第三，我们建议将这个化合物(S)注射到 一种新的敲击小鼠系，其中PHD2基因具有人源化的锌指，以便 与体外研究确定的化合物的相互作用。因此，本应用程序涉及一个 将福克斯大通化学公司的药物化学专业知识结合在一起的合作伙伴关系 多样性中心与哥伦比亚大学首席研究员实验室的经验 宾夕法尼亚州在研究低氧诱导因子途径。该项目的长期目标将是确定一个 可以在更详细的IND指导研究中进行评估的临床前候选药物。这样的一个 候选药物将成为治疗贫血的有前途的药物。

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.