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:
- 金额:$ 11.26万
- 依托单位:
- 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:
- 关键词:ARNT geneAnemiaAttentionBindingBinding SitesBiochemicalBiological AssayBiological AvailabilityBloodBone MarrowCardiovascular DiseasesCatalogsCellsChronic Kidney FailureClinical TrialsComplexComplicationCrystallizationDevelopmentDiseaseDoseDrug or chemical Tissue DistributionEnzymesErythrocytesErythropoiesisErythropoietinGenesGlycoproteinsHormonesHospitalizationHydrophobicityHypoxiaHypoxia Inducible FactorImpaired cognitionInjectionsKidneyKnowledgeLibrariesLigand BindingLiverMeasuresMolecularNIH Program AnnouncementsNational Institute of Diabetes and Digestive and Kidney DiseasesOxygenPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPhysiologicalProcollagen-Proline DioxygenaseProductionProtein SubunitsProteinsQuality of lifeRecombinant ErythropoietinResponse ElementsStressStructureTestingTherapeuticTherapeutic AgentsToxic effectTranscriptional ActivationUnited StatesUnited States National Institutes of HealthX-Ray Crystallographyadverse outcomeassay developmentbHLH-PAS factor HLFbasecytokinedesignexperiencefollow-uphigh throughput screeningimaging agentinhibitor/antagonistinterestlead optimizationmortalitynovel therapeuticspreclinical developmentprotein protein interactionresponsescreeningsmall moleculesmall molecule librariestherapeutic targettranscription 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
项目成果
期刊论文数量(0)
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FRAYDOON RASTINEJAD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
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9113818 - 财政年份:2016
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Identification of Allsoteric Ligands for Hepatic Nuclear Factor 4-alpha
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- 资助金额:
$ 11.26万 - 项目类别:
Identification of Allsoteric Ligands for Hepatic Nuclear Factor 4-alpha
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Structural Characterization of Metabolic Gene Regulators
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8728842 - 财政年份:2011
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Structural Characterization of Metabolic Gene Regulators
代谢基因调控因子的结构表征
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8339923 - 财政年份:2011
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Structural Characterization of Metabolic Gene Regulators
代谢基因调控因子的结构表征
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8538964 - 财政年份:2011
- 资助金额:
$ 11.26万 - 项目类别:
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