HDAC-IN-84-生命科学试剂-MCE

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEHDAC-IN-84Cat.No.:HY-170379分⼦式:C₁₇H₂₁N₃O₅S分⼦量:379.43作⽤靶点:HDAC;Apoptosis作⽤通路:CellCycle/DNADamage;Epigenetics;Apoptosis储存⽅式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY⽣物活性HDAC-IN-84(compound4a)⼀种强效的HDAC抑制剂，HDAC1，HDAC2，HDAC3，HDAC6，HDAC8和HDAC11的IC50值分别为0.0045,0.015,0.013,0.038,5.8和26μM。HDAC-IN-84能有效抑制⽩⾎病细胞的增殖⽽不引起毒性[1]。IC50&TargetHDAC1HDAC2HDAC-3HDAC40.0045μM(IC50)0.015μM(IC50)0.013μM(IC50)>100μM(IC50)HDAC6HDAC8HDAC110.038μM(IC50)5.8μM(IC50)26μM(IC50)体外研究HDAC-IN-84(95min)inhibitsHDAC1,HDAC2,HDAC3,HDAC4,HDAC6,HDAC8andHDAC11withIC50valuesof0.0045,0.015,0.013,>100,0.038,5.8and26μM,respectively[1].HDAC-IN-84(0.005-25μM,72h)inhibitsHL60,HPBALL,andK562cellswithIC50sof76.8,110.6and180.8nMrespectively[1].HDAC-IN-84(0.25μM,48h)resultsinnotableα-tubulinacetylationandhigherPARPcleavageofHDAC6[1].HDAC-IN-84(0.25μM,48h)inducesApoptosisinHL60cells[1].HDAC-IN-84(0.15-0.2μM,24h)inducescellcyclearrestinHL60cells[1].HDAC-IN-84(2.5,50nM,1μM,24h)demonstratesexcellentstabilityoverthe24hperiodmonitoredinhumanplasmaat37°C[1].HDAC-IN-84(2.5,50nM,1μM,48h)bindswithplasmaproteinwithameanof99.0%overtheobservedconcentrationrangewithnoconcentration-dependency[1].HDAC-IN-84(0-1μM)inhibitsMV4-11cellswithanIC50of0.036μM,exhibitingovera7-foldincreaseinpotencycomparedtoVorinostat(HY-10221)[1].1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEHDAC-IN-84(0-10μM,72h)andVorinosta(HY-10221)affectsC1498cellgrowthinaconcentration-dependentmannerwithIC50sof0.425and1.06μM,respectively[1].ComparisonofInVitroPharmacokineticDataofHDAC-IN-84toVorinostatasvorinostatasHDAC-IN-84logD1.461.47plasmastability/t1/275min>24hKB/P2.01.26plasmaproteinbinding71%99%microsomalstability/t1/2(clearancecategory)60min35.9minApoptosisAnalysis[1]CellLine:HL60cellsConcentration:0.25μMIncubationTime:48hResult:InducedApoptosis,leadingtocytotoxicimpactsonleukemiacells.CellViabilityAssay[1]CellLine:K562,HL60,HPBALLcellsConcentration:0.005-25μMIncubationTime:72hResult:InhibitedHL60,HPBALL,andK562cellswithIC50sof76.8,110.6and180.8nMrespectively.WesternBlotAnalysis[1]CellLine:HL60cellsConcentration:0.25μMIncubationTime:48hResult:Resultedinnotableα-tubulinacetylation(indicatingeffectiveinhibition)ofHDAC6.ResultedinhigherPARPcleavage(indicatorofapoptosisinduction).CellCycleAnalysis[1]CellLine:HL60cellsConcentration:0.15,0.2μMIncubationTime:24hResult:Inducedcellcyclearrestinleukemiacells.体内研究HDAC-IN-84(10mg/kg,i.p.,daily,14days)suppressesMV4-11andC1498cellsgrowthinapreclinicalleukemicxenograftmouse(NSG)model[1].2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEHDAC-IN-84(10mg/kg,i.p.)ischaracterizedbyashorteliminationhalf-lifeof0.35hinthreeC57BL/6mice.[1].HDAC-IN-84(20mg/kg,i.p.,daily,21days)exhibitssignificantlylowerleukemiaburden,withnosignificantdifferencesinbodyweightinallograftleukemiamodel[1].PharmacokineticParameters(AUClast,Cmax,Tmax,andt1/2)WereCalculatedAccordingtoaNoncompartmentalAnalysis(NCA)fromtheBloodConcentrationofHDAC-IN-84BasedonActualBloodSamplingTimePre-DoseandPost-Dosevariablemouse1mouse2mouse3mean[±SD]VorinostatVorinostatintraperitoneal10mg/kgperoral50mg/kgCmax(ng/mL)1490103012301250[±232]501580Tmax(h)50.25[±0]na0.08AUClast(h·ng/mL)523396480466[±65]619347t1/20.2750.5540.2270.352[±0.177]0.750.8AnimalModel:preclinicalleukemicxenograftmouse(NSG)model.Eachmousereceived0.5×106MV4-11luc-GFP+leukemiccells.Afterconfirmationoftumorengraftmentviamonitoringbioluminescence-basedinvivoimagingsystem(IVIS)[1].Dosage:10mg/kgAdministration:i.p.,daily,42daysResult:SignificantlysuppressedtheinvivogrowthofMV4-11leukemiacellsascomparedtothevehiclecontrol.Exhibitedaminor(notsignificant)reductioninbodyweight.AnimalModel:Allograftleukemiamodel.Inthismodel,leukemiaisestablishedbyinjecting(C57BL/6)derivedmurineAML(C1498)cellsbyintravenousinjectioninimmunocompetentwildtpye(C57BL/6)mice[1].Dosage:20mg/kgAdministration:i.p.,daily,21daysResult:Exhibitedsignificantlylowerleukemiaburdenafterthesecondtreatmentcycle,withthisdifferencebecomingmorepronouncedbyday19.Nosignificantdifferencesinbodyweightwereobservedduringthetreatmentcourse.REFERENCES[1].FischerF,et.al.DecipheringtheTherapeuticPotentialofNovelPentyloxyamide-BasedClassI,IIbHDACInhibitorsagainstTherapy-ResistantLeukemia.JMed