USE OF DYRK1A/B KINASE INHIBITORS FOR THE TREATMENT OF LIVER DISEASES
使用 DYRK1A/B 激酶抑制剂治疗肝病
基本信息
- 批准号:10696380
- 负责人:
- 金额:$ 34.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlzheimer&aposs DiseaseAnimal Disease ModelsAnti-Inflammatory AgentsAntidiabetic DrugsAntioxidantsAreaAttentionBiochemicalBiological AvailabilityBiological MarkersBiological SciencesBody WeightCOL1A1 geneCell ProliferationCellular AssayCirrhosisCollaborationsCollagenCyclin D1CyclodextrinsCytoprotectionDataDepositionDevelopmentDiabetes MellitusDietDisease ProgressionDistressDoseDown SyndromeDrug ExposureDrug KineticsDrug Metabolic DetoxicationDrug TargetingEatingEnhancersExhibitsExtracellular MatrixFABP1 geneFDA approvedFamily memberFatty AcidsFatty LiverFibrosisFormulationFoundationsGenesGlial Fibrillary Acidic ProteinGoalsHalf-LifeHealth PromotionHepaticHepatic Stellate CellHepatotoxicityHigh Fat DietHistologicHypertriglyceridemiaIn VitroInflammationInflammatoryInsulin ResistanceInterferon Type IILeadLiverLiver FibrosisLiver diseasesMeasuresMediatingMetabolic DiseasesModelingMolecular TargetMusNQO1 geneNon-Insulin-Dependent Diabetes MellitusObesityOncologyOralOrganOutcomeOxidation-ReductionPancreasPathologicPathologyPathway interactionsPeripheralPharmaceutical ChemistryPharmaceutical PreparationsPharmacological TreatmentPharmacotherapyPhasePhase I Clinical TrialsPhosphorylationPhosphotransferasesPioglitazonePlasmaPopulationPrimary carcinoma of the liver cellsProductionProteinsProxyPublic HealthReactive Oxygen SpeciesRegimenResearchRoleRouteSafetySmall Business Innovation Research GrantSpecificitySteatohepatitisStructure of beta Cell of isletTestingTherapeuticTimeToxic effectTranslational ResearchTyrosineTyrosine PhosphorylationVascular Endothelial Growth FactorsVitamin EWorkanimal efficacycell growth regulationchronic liver diseasecombatcytokinedrug mechanismefficacy testingend stage liver diseasefibrogenesisimprovedin vitro activityin vivoinhibitorinnovationinsightinterestkinase inhibitorlipid biosynthesisliver inflammationliver injuryliver transplantationmouse modelnephrotoxicitynervous system disorderneuroinflammationneuronal survivalneuroprotectionnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelnovel therapeuticsnuclear factor-erythroid 2nuclear factors of activated T-cellspharmacokinetics and pharmacodynamicspharmacologicphase 1 studyresponsesafety studysmall molecule inhibitortherapeutic targettranscription factoruptake
项目摘要
PROJECT SUMMARY
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. One-fourth of the adult
population suffers from NAFLD worldwide. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, can
progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause of end-stage liver disease
and liver transplantation. Liver fibrosis is a major consequence of chronic liver disease, where the excess extracellular
matrix is deposited, which is caused by the activation of hepatic stellate cells (HSCs). There is an urgent public health need
to develop safe and effective pharmacological treatments to alleviate hepatic inflammation, fibrosis, and steatohepatitis.
However, there are no FDA-approved medications for NAFLD.
This SBIR Phase I proposal seeks to evaluate ABI-171, a novel compound with demonstrated selectivity for
DYRK1A and its close family member DYRK1B in biochemical and cellular assays. ABI-171 exhibits pharmacological
activity with evidence of efficacy in several animal models of disease. We hypothesize that its broad anti-inflammatory and
cytoprotective activities combined with its potential health-promoting activities to thwart diabetes, reduce fatty acid uptake,
and suppress collagen accumulation may effectively combat NAFLD.
In this Phase I study, two specific aims are proposed: in Aim 1 we will evaluate the accumulation of ABI-171 in
the organs of interest, namely the liver, to advance its safety profile. In Aim 2, we will test the efficacy of ABI-171 in the
high-fat diet model of NASH, which is well-established for providing mechanistic insight of treatments and its potential for
research translation. Detailed readouts for this study will be bodyweight and food intake, insulin resistance, liver injury
biomarkers, liver pathology including histological and biochemical assessments, and expression levels of genes and proteins
involved in DYRK1A/1B-mediated regulation of cellular cytoprotection, inflammation, lipogenesis, and fibrogenesis.
The successful completion of this application will significantly advance the efficacy and mechanism of action of
our selective DYRK inhibitor in NASH, thus forming strong foundation for a Phase 2 project in which drug activity will be
examined in more detail for the treatment of metabolic disorders and complete the development work needed to move ABI-
171 into an early-stage clinical trial.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gian Luca Araldi其他文献
Gian Luca Araldi的其他文献
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{{ truncateString('Gian Luca Araldi', 18)}}的其他基金
Development of DYRK1A allosteric modulator for the treatment of Alzheimer’s Disease
开发用于治疗阿尔茨海默病的 DYRK1A 变构调节剂
- 批准号:
9932627 - 财政年份:2019
- 资助金额:
$ 34.92万 - 项目类别:
Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的 DYRK1A 变构调节剂
- 批准号:
10708925 - 财政年份:2017
- 资助金额:
$ 34.92万 - 项目类别:
Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的 DYRK1A 变构调节剂
- 批准号:
9925159 - 财政年份:2017
- 资助金额:
$ 34.92万 - 项目类别:
Development of DYRK1A allosteric modulator for the treatment of Alzheimer's Disease
开发用于治疗阿尔茨海默病的 DYRK1A 变构调节剂
- 批准号:
10601148 - 财政年份:2017
- 资助金额:
$ 34.92万 - 项目类别:
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