Hotline:400-820-3792Inhibitors ? ScreeningLibraries ? Proteinswww.MedChemENCI-006Cat.No.:HY-176798CASNo.:1964516-64-0分子式:C??H??F?N?O?S?分子量:650.74作用靶點:LactateDehydrogenase;ReactiveOxygenSpecies(ROS);Apoptosis作用通路:MetabolicEnzyme/Protease;Immunology/Inflammation;NF-κB;Apoptosis儲存方式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY生物活性NCI-006是一種具有口服活性的乳酸脫氫酶(LDH)抑制劑(LDHAIC50=0.06μM;LDHBIC50=0.03μM)。NCI-006在小鼠胰腺癌模型中抑制了腫瘤內(nèi)LDH活性、乳酸生成、腫瘤生長。NCI-006在體外抑制糖酵解，誘導(dǎo)細胞凋亡(apoptosis)。NCI-006與電離輻射(IR)結(jié)合使用可以增強糖酵解腫瘤細胞系的放射敏感性，同時不影響非糖酵解/正常細胞(1522，皮膚成纖維細胞)。NCI-006與IACS-010759(HY-112037)聯(lián)合使用對結(jié)直腸癌和胃癌發(fā)揮協(xié)同抗腫瘤作用。NCI-006通過抑制乳酸脫氫酶靶向糖酵解會損害尤文肉瘤模型中的腫瘤生長。體外研究NCI-006(0-1μM)inhibitstheactivityofhumanLDH(hLDH),andtheHEK293Tcellsisoenzymes2,3,4,5andmouseisoenzymes1,2,3,4,5,doesnotinhibittheactivityofmalatedehydrogenase(MDH)andsuccinatedehydrogenase(SDH)isolatedfromhumankidney[3].NCI-006(0.2-5μM,2h)reducestheNAD/NADHratioinMIAPaCa-2andHT29cells,affectslactatesecretioninmouse(m)andhuman(h)redbloodcells(RBCs)aswellasMIAPaCa-2andHT29cells,withEC50sof1.6,2.1,0.37,0.53μM[3].NCI-006(0-10μM,0-180min)reducesthebasalextracellularacidificationrate(ECAR)inatime-dependentmannerataminimumconcentrationof1μMandinhibitsglycolysisatconcentrations≥1μM,andimprovesbasicoxygenconsumptionrate(OCR)inMIAPaCa-2cells[3].NCI-006(1μM)combinedwithIACS-010759(HY-112037)reducescellviabilityinMIAPaCa-2,HCT116,andMKN45cells[3][6].NCI-006(5μM)reducesOCR,ECAR,sugarATPproductionrate,hasnochangeofmitoATPproductionrateortotalATPproductionrate,doesnotincreasemitoticATPproductionrate,butsignificantlyincreasessugarATPproductionrateincombinationwithIACS-010759(HY-112037)inHCT116andMKN45cells[6].NCI-006(72h)inhibitsewingsarcomacelllinesproliferation,withIC50srangingfrom100nmol/L(TC71and1/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemETC32)to1μmol/L(RDESandEW8),hasnoeffectofrhabdomyosarcomaandosteosarcoma,withanIC50of1037nmol/L[7].NCI-006dose-dependentlyinhibitsLDHactivityinTC71,TC32,EW8cells,withIC50sapproximately100nmol/L[7].NCI-006(0.1-10μM,2h)inhibitsECARinTC71andEW8cells[7].體內(nèi)研究NCI-006(0-200mg/kg,p.o./i.v.,once)reducesLDHactivityat2hinfemaleathymicnudemice[3].NCI-006(50mg/kg,p.o./i.v.,once;i.v.,everyotherdayfor1week,orfor2weeks)inhibitstumorLDHactivity,resultingindecreasedconversionofpyruvatetolactate,withenhancedpyruvatefluxtobicarbonateandmitochondrialoxidation,withoutadetectableincreaseintransaminase-mediatedpyruvatefluxtoalanine,slowsthetumorgrowthinMIAPaCa-2/HT29tumorfemaleathymicnudemice[3].NCI-006(40mg/kg,i.v.,2/3timesaweek,1/2weeks)treatmentalonedoesnotinhibittumorgrowth,inhibitstumorgrowthincombinationwithIACS-010759(HY-112037)inHCT116andMKN45xenograftsnudemice[6].NCI-006(50mg/kg,p.o.,onceortwicedaily,3weeks)haslittlechangeintumorgrowthinTC71,TC32,andEW8xenograftsfemaleFoxChaseSCIDbeigemice[7].AnimalModel:Femaleathymicnudemice(20-25g)[3]Dosage:0mg/kg,10mg/kg,50mg/kg,100mg/kg,200mg/kgAdministration:p.o.,onceResult:Dose-dependentreducedLDHactivityat2h,butinmostcases,recoverytobaselinelevelsby24h,75%-80%ofbaselineat24h,withmaximalinhibitionmaintainedat8h.AnimalModel:Femaleathymicnudemice(20-25g)[3]Dosage:0mg/kg,10mg/kg,25mg/kg,50mg/kg,100mg/kgAdministration:i.v.,onceResult:Dose-dependentreducedLDHactivityat2h,butinmostcases,recoverytobaselinelevelsby24h.AnimalModel:MIAPaCa-2tumorfemaleathymicnudemice(20-25g)[3]Dosage:50mg/kgAdministration:p.o./i.v.,once;i.v.,everyotherdayfor1week(threeinjections,Monday,Wednesday,andFriday),orfor2weeks(sixinjections)withabreakof1weekbetweencycles.Result:InhibitsLDHby80%atintratumoraldruglevelsofapproximately20μM.Dosedependentlysuppressedthetumor[13C]lactate/[13C]pyruvateratio,didnotaffectthe[13C]lactate/[13C]pyruvateratioinMIAPaCa-2tumors(upto7hafterdrugadministration).2/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemESlowedthegrowthofMIAPaCa-2xenograftswithoutamarkedeffectonmousebodyweight.Reducedconversionof[13C]pyruvatetoboth[13C]lactateand[13C]bicarbonate,moresignificantlyinhibitstumorgrowthincombinationwithIACS-010759(HY-112037).AnimalModel:HT29tumorfemaleathymicnudemice(20-25g)[3]Dosage:50mg/kgAdministration:i.v.,onceResult:Decreasedthe[13C]Lac/[13C]Pyrratioby74.7%.MoresignificantlyinhibitstumorgrowthwhencombinedwithMetformin(HY-B0627).AnimalModel:HCT116(5×106)xenograftsnudemice(18-24g,six-week-oldfemaleKSN/slcathymic)[6]Dosage:40mg/kgAdministration:i.v.,3timesaweek,1weeksResult:Treatmentalonedidnotinhibittumorgrowth,inhibitedtumorgrowthandtransientlyandsignificantlyincreasedAST,ALT,amylase,lipase,creatinine,andbilirubinlevelsincombinationwithIACS-010759(HY-112037).Decreasedthe13C-L/Pratio,increasedROSlevels.AnimalModel:MKN45xenograftsnudemice(18-24g,six-week-oldfemaleKSN/slcathymic)[6]Dosage:40mg/kgAdministration:i.v.,2timesaweek,2weeksResult:Treatmentalonedidnotinhibittumorgrowth,inhibitedtumorgrowthandtransientlyandsignificantlyincreasedAST,ALT,amylase,lipase,creatinine,andbilirubinlevelsincombinationwithIACS-010759(HY-112037).Decreasedthe13C-L/Pratio.AnimalModel:TC71,TC32,andEW8xenograftsfemaleFoxChaseSCIDbeigemice[7]Dosage:50mg/kgAdministration:p.o.,onceortwicedaily,3weeksResult:Hadlittlechangeintumorgrowth.REFERENCES3/4 MasterofBioactiveMolecules—您身邊的抑制劑大師www.MedChemENobuOshima,etal.Abstract6222:Comprehensivemonitoringofpyruvatemetabolismincancercellsandtumorsrevealsvulnerabilitytometabolicinhibitiontherapywithsmallmolecules.CancerRes15June2022;82(12_Supplement):6222.NobuOshima,etal.Abstract2783:MonitoringofanovelLDHinhibitorandmitochondrialinhibitorefficacyinvivoinaglycolyticpancreaticcancermodelusinghyperpolarized13CMRI.CancerRes15August2020;80(16_Supplement):2783.OshimaN,etal.DynamicImagingofLDHInhibitioninTumorsRevealsRapidInVivoMetabolicRewiringandVulnerabilitytoCombinationTherapy.CellRep.2020Feb11;30(6):1798-1810.e4.RaiG,etal.DiscoveryandOptimizationofPotent,Cell-ActivePyrazole-BasedInhibitorsofLactateDehydrogenase(LDH).JMedChem.2017Nov22;60(22):9184-9204.SuchetTaori,etal.Abstract3587:Targetingcanc