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

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

项目成果

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FRAYDOON RASTINEJAD其他文献

FRAYDOON RASTINEJAD的其他文献

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{{ truncateString('FRAYDOON RASTINEJAD', 18)}}的其他基金

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:
    9906953
  • 财政年份:
    2018
  • 资助金额:
    $ 11.26万
  • 项目类别:
Structural Biology of Multi-Domain Nuclear Receptor Complexes
多域核受体复合物的结构生物学
  • 批准号:
    9159659
  • 财政年份:
    2017
  • 资助金额:
    $ 11.26万
  • 项目类别:
Molecular Characterization of Mammalian bHLH-PAS Transcription Factors
哺乳动物 bHLH-PAS 转录因子的分子表征
  • 批准号:
    9324331
  • 财政年份:
    2016
  • 资助金额:
    $ 11.26万
  • 项目类别:
Molecular Characterization of Mammalian bHLH-PAS Transcription Factors
哺乳动物 bHLH-PAS 转录因子的分子表征
  • 批准号:
    9113818
  • 财政年份:
    2016
  • 资助金额:
    $ 11.26万
  • 项目类别:
Identification of Rev-Erb alpha/beta nuclear receptor modulators
Rev-Erb α/β 核受体调节剂的鉴定
  • 批准号:
    8671893
  • 财政年份:
    2014
  • 资助金额:
    $ 11.26万
  • 项目类别:
Identification of Allsoteric Ligands for Hepatic Nuclear Factor 4-alpha
肝核因子 4-α 变构配体的鉴定
  • 批准号:
    8421932
  • 财政年份:
    2012
  • 资助金额:
    $ 11.26万
  • 项目类别:
Identification of Allsoteric Ligands for Hepatic Nuclear Factor 4-alpha
肝核因子 4-α 变构配体的鉴定
  • 批准号:
    8775220
  • 财政年份:
    2012
  • 资助金额:
    $ 11.26万
  • 项目类别:
Structural Characterization of Metabolic Gene Regulators
代谢基因调控因子的结构表征
  • 批准号:
    8728842
  • 财政年份:
    2011
  • 资助金额:
    $ 11.26万
  • 项目类别:
Structural Characterization of Metabolic Gene Regulators
代谢基因调控因子的结构表征
  • 批准号:
    8339923
  • 财政年份:
    2011
  • 资助金额:
    $ 11.26万
  • 项目类别:
Structural Characterization of Metabolic Gene Regulators
代谢基因调控因子的结构表征
  • 批准号:
    8538964
  • 财政年份:
    2011
  • 资助金额:
    $ 11.26万
  • 项目类别:

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