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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：
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
项目类别：
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

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.

项目总结