Identification of Hypoxia-Inducible Factor-2alpha Activators for Chronic Kidney Disease Anemia

慢性肾病贫血缺氧诱导因子 2α 激活剂的鉴定

基本信息

批准号：
9906953
负责人：
FRAYDOON RASTINEJAD
金额：
$ 35.15万
依托单位：
UNIVERSITY OF OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906953
关键词：
ARNT gene Anemia Attention Binding Binding Sites Biochemical Biological Assay Biological Availability Blood Bone Marrow Cardiovascular Diseases Catalogs Cells Chronic Kidney Failure Clinical Trials Complex Complication Crystallization Development Disease Dose Drug or chemical Tissue Distribution Enzymes Erythrocytes Erythropoiesis Erythropoietin Genes Glycoproteins Hormones Hospitalization Hydrophobicity Hypoxia Hypoxia Inducible Factor Impaired cognition Injections Kidney Knowledge Libraries Ligand Binding Liver Measures Molecular NIH Program Announcements National Institute of Diabetes and Digestive and Kidney Diseases Oxygen Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Procollagen-Proline Dioxygenase Production Protein Subunits Proteins Quality of life Recombinant Erythropoietin Response Elements Stress Structure Testing Therapeutic Therapeutic Agents Toxic effect Transcriptional Activation United States United States National Institutes of Health X-Ray Crystallography adverse outcome assay development bHLH-PAS factor HLF base cytokine design experience follow-up high throughput screening imaging agent inhibitor/antagonist interest lead optimization mortality novel therapeutics preclinical development protein protein interaction response screening small molecule small molecule libraries therapeutic target transcription factor

项目摘要

PROJECT SUMMARY Anemia is a common and significant complication of chronic kidney disease (CKD), leading to multiple adverse consequences including, increased hospitalizations and mortality, cardiovascular disease, cognitive impairment, and diminished quality of life. Nearly half of all patients with stage 3-5 CKD experience anemia. In these patients, the underlying cause is from the diminished kidney production of erythropoietin (EPO). EPO is a glycoprotein cytokine secreted by the kidney in response to low oxygen stress to stimulate red blood cell production in the bone marrow. The hypoxia-inducible factor-2 alpha (HIF-2) forms heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to form a productive transcription factor that drives physiological EPO expression by binding to the hypoxia response element (HRE) upstream of the EPO gene. Our detailed structural elucidation of the multi-domain heterodimeric complex of HIF-2/ARNT has allowed Certain small-molecules such as PT2385 and OX3 can act as inhibitors of HIF-2 by disrupting the HIF-2/ARNT heterodimer. We hypothesize that other small-molecules can be identified to stabilize the HIF-2/ARNT heterodimer and act as activators. However, no attempts have yet been undertaken to identify HIF-2 activators. Driven by our recent crystallographic discovery of multiple ligand-binding cavities within this heterodimer, we designed and conducted small pilot screens based on a sensitive biochemical protein-protein interaction assay. These efforts allowed the identification of small- molecules that biochemically stabilize the HIF-2/ARNT heterodimer and led to enhanced EPO expression within cells. In response to new appreciation for its drug-binding potentials. NIDDK PA-16-374, we now propose to conduct a comprehensive high-throughput screen using a 350,000-compound library, together with the suite of secondary and tertiary confirmatory assays to identify HIF-2/-ARNT selective activators for preclinical development. These activators will have substantial advantages over the current treatments involving recombinant EPO injections, and should be significantly safer and more effective than the prolyl-hydroxylase inhibitors undergoing development.

项目摘要贫血是慢性肾脏疾病（CKD）的常见且显着的并发症，导致多个对立后果包括增加住院和死亡率，心血管疾病，认知损害和生活质量降低。在所有患有3-5阶段CKD期患者中，几乎一半患有贫血。在这些患者的根本原因来自促红细胞生成素（EPO）的肾脏产生。 EPO是肾脏分泌的糖蛋白细胞因子响应低氧应激以刺激红细胞在骨髓中产生。低氧诱导因子-2α（HIF-2）与芳基形成异二聚体碳氢化合物受体核转运剂（ARNT）形成驱动的生产转录因子通过与EPO基因上游的缺氧反应元件（HRE）结合来表达生理EPO。我们的 HIF-2/ARNT的多域异构体复合物的详细结构阐明已允许某些小分子（例如PT2385和OX3）可以充当通过破坏HIF-2/ARNT异二聚体的抑制剂。我们假设其他小分子可以识别以稳定HIF-2/ARNT异二聚体并充当激活剂。但是，没有尝试然而，被禁止识别HIF-2激活剂。在我们最近的晶体学发现的驱动下该异二聚体内的配体结合腔，我们根据A设计并进行了小型飞行员屏幕敏感的生化蛋白 - 蛋白质相互作用测定法。这些努力允许确定小型生化稳定HIF-2/ARNT异二聚体并导致EPO表达增强的分子在细胞内。响应对其药物结合潜力的新欣赏。 NIDDK PA-16-374，我们现在建议进行全面的高通量使用350,000个复合库的屏幕，以及次要和第三级确认的套件识别临床前开发的HIF-2/-AR-AR-AR-AR-AR-AR-AR-AR-AR-AR-AR-AR-AR-AR。这些激活器将有与当前治疗相比，涉及重组EPO注射的实质优势，应为与正在发育的丙酰羟化酶抑制剂相比，明显更安全，更有效。