Next generation HDAC inhibitors with superior potency, selectivity, and pharmacokinetic profiles for the treatment of liver ischemia-reperfusion injury
Next generation HDAC inhibitors with superior potency, selectivity, and pharmacokinetic profiles for the treatment of liver ischemia-reperfusion injury
批准号:
9907822
负责人:
Chung-Jen James Chou
金额:
$29.54万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-09-17 至 2021-08-31
关键词:
AbdomenAcuteAcute Liver FailureAddressAntineoplastic AgentsAttenuatedBindingBiological AvailabilityCell DeathCessation of lifeClinicClinicalDataDiseaseDoseDrug KineticsExcisionFDA approvedGoalsHDAC1 geneHemorrhagic ShockHepaticHistone DeacetylaseHistone Deacetylase InhibitorHydrogen BondingHydrophobic InteractionsIn VitroInflammationInjectionsKetonesLeadLength of StayLinkLiverLiver DysfunctionMedicalMetalsMitochondriaModelingModificationMolecular StructureMolecular TargetMultiple Organ FailureMusNiacinamideOperative Surgical ProceduresOralOutcomePharmaceutical PreparationsPlayPredispositionPreventionPrevention therapyPropertyProtein IsoformsRecoveryReperfusion InjuryReperfusion TherapyResuscitationRiskRouteSafetyShockSolubilityStructureTestingTimeToxic effectTransaminasesTransplantationTraumaTreatment EfficacyVascular DiseasesWorkanalogaqueouscomparative efficacydosageeffective therapygraft failureimprovedin vivoinjury preventioninnovationlead candidateliver functionliver inflammationliver injuryliver ischemialiver transplantationmitochondrial dysfunctionmortalitynanomolarnew therapeutic targetnext generationnovelnovel therapeuticsparenteral administrationpreventside effectsuccesstumorusability
中文摘要
肝缺血/再灌注损伤(IRI)发生在许多临床情况,如创伤,肝脏手术
英文摘要
Hepatic ischemia/reperfusion injury (IRI) occurs in many clinical situations, such as trauma, hepatic surgery
(e.g. liver resection for tumor treatment, liver donation and transplantation), shock and vascular diseases.
Hepatic I/R causes severe liver injury and promotes inflammation, leading to liver dysfunction, multiple organ
failure and death. It also compromises long-term outcomes after surgery and trauma. Currently, no effective
therapy is available for hepatic IRI prevention/treatment. Recently we identified a class of novel histone
deacetylase inhibitor (HDACI) working through both allosteric and competitive mechanisms. The lead
compounds in this class are more potent and have better pharmacokinectic (PK) properties and lower predicted
toxicity profile than all current FDA-approved HDACI. Moreover, we recently showed that a lead compound, LP-
411, blocks mitochondrial dysfunction and attenuates liver injury and inflammation after hepatic I/R. In the clinic,
a parenteral administered route is needed for IRI. Thus, our goal is to generate a lead HDACI with high
potency and selectivity, low predicted toxicity, and optimized PK for parenteral injection by modification
of the molecular structure of LP-411, thus generating a new HDACI that can effectively decrease hepatic
IRI in vivo and is suitable for clinical use. In Aim 1, we will generate new HDACI by optimizing the structure
of LP-411 for parenteral administration. We will also replace the potential toxic α,β-unsaturated ketone with
aromatic heterocyclic groups, and improve HDAC selectivity with more selective metal-binding groups while
maintaining the geometric, hydrogen bonding, and hydrophobic interaction. The potency of HDAC inhibition and
HDAC selectivity will be tested to select new lead compounds. Aqueous solubility and predicted toxicity, and in
vivo PK properties for parenteral injection of the new lead compound will be determined. We expect that this
study will generate new lead candidates that have better selectivity, potency, solubility, and PK properties for
parenteral administration but lower predicted toxicity compared to LP-411. The current lead candidate LP-411
markedly decreases liver injury and inflammation after hepatic I/R, suggesting that HDAC inhibition is a novel,
effective therapeutic strategy. Therefore in Aim 2, we will determine the efficacy as a proof of concept study for
the new lead HDACI candidate to prevent/treat hepatic IRI in vivo using a widely accepted mouse I/R model.
After determination of the maximum tolerated dosage, we will examine the effects of the new lead candidate on
cell death, transaminase release, liver function, inflammation and survival after hepatic I/R. We will also elucidate
whether these novel HDACI can be used only in elective surgery or can be used in both elective surgery and
unpredictable acute situations (e.g., trauma) by comparing the efficacy of pre-ischemic and post-ischemic
treatment. The success of this study will identify a novel therapeutic strategy and develop much-needed, effective
new drugs for prevention/treatment of hepatic IRI, thus decreasing mortality and improving clinical outcomes in
surgery, trauma and other diseases related to liver IRI.
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Treatment of liver fibrosis with oral hepatic stable and non-genotoxic HDAC inhibitors
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批准号:10323753
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项目类别:
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资助金额:$34.99万
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财政年份:2021
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Novel lysine deacetylase 6 Hsp domain inhibitors against AML
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批准号:8828118
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资助金额:$31.02万
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负责人:Chung-Jen James Chou
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依托单位:
Novel lysine deacetylase 6 Hsp domain inhibitors against AML
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资助金额:$30.09万
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负责人:Chung-Jen James Chou
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依托单位:
海外基金