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

• 批准号: 9577222
• 负责人: FRAYDOON RASTINEJAD
• 金额: $ 11.26万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2018-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9577222
• 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

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.

项目总结 贫血是慢性肾脏疾病(CKD)的常见和重要并发症，导致多种不良反应 后果包括，住院和死亡率增加，心血管疾病，认知 损害和生活质量下降。 所有3-5期CKD患者中，近一半经历了贫血。在……里面 这些患者的根本原因是肾脏产生的促红细胞生成素(EPO)减少。EPO是 一种糖蛋白细胞因子，由肾脏分泌，以响应低氧应激刺激红细胞 在骨髓中产生。缺氧诱导因子-2α(HIF-2)与芳基形成异二聚体 碳氢受体核转运体(ARNT)形成一种生产性转录因子，驱动 通过与EPO基因上游的缺氧反应元件(HRE)结合来实现生理性EPO的表达。 我们的 HIF-2/ARNT多结构域异二聚体的详细结构解析 某些小分子，如PT2385和OX3，可以作为 通过破坏HIF-2/ArnT异源二聚体来抑制。我们假设其他小分子 可以稳定HIF-2/ARNT异源二聚体，并作为激活剂。然而，没有任何尝试 目前已着手确定低氧诱导因子-2激活剂。由我们最近发现的多个 在这个异源二聚体中的配基结合腔，我们设计并进行了基于 灵敏的生化蛋白质-蛋白质相互作用分析。这些努力使得能够识别小规模的- 生化稳定缺氧诱导因子-2/ArnT异源二聚体并导致促红细胞生成素表达增强的分子 在细胞内。作为对.的回应 对其药物结合潜力的新评价。 NIDDK PA-16-374，我们现在建议进行全面的高通量 筛选使用了350,000个化合物文库，以及二级和三级确证套件 鉴定HIF-2/-ARNT选择性激活剂用于临床前开发的试验。这些激活剂将有 与目前涉及重组促红细胞生成素注射的治疗相比，具有实质性的优势，并且应该是 比正在开发的Pro-羟基酶抑制剂更安全、更有效。