Tipifarnib-IND-58359-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemETipifarnibCat.No.:HY-10502CASNo.:192185-72-1Synonyms:IND58359;R115777分⼦式:C₂₇H₂₂Cl₂N₄O分⼦量:489.4作⽤靶点:FarnesylTransferase作⽤通路:MetabolicEnzyme/Protease储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:14.29mg/mL(29.20mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.0433mL10.2166mL20.4332mL5mM0.4087mL2.0433mL4.0866mL10mM0.2043mL1.0217mL2.0433mL请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；⼀旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存⽅式和期限：-80°C,6months;-20°C,1month。-80°C储存时，请在6个⽉内使⽤，-20°C储存时，请在1个⽉内使⽤。体内实验请根据您的实验动物和给药⽅式选择适当的溶解⽅案。以下溶解⽅案都请先按照InVitro⽅式配制澄的储备液，再依次添加助溶剂：(为保证实验结果的可靠性，澄的储备液可以根据储存条件，适当保存；体内实验的⼯作液，建议您现⽤现配，当天使⽤；以下溶剂前显⽰的百分⽐指该溶剂在您配制终溶液中的体积占⽐；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的⽅式助溶)1.请依序添加每种溶剂：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥1.43mg/mL(2.92mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:1.43mg/mL(2.92mM);Suspendedsolution;Needultrasonic3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥1.43mg/mL(2.92mM);Clearsolution4.请依序添加每种溶剂：20%HP-β-CD/10mMcitratepH2.0Solubility:10mg/mL(20.43mM);Clearsolution;NeedultrasonicBIOLOGICALACTIVITY⽣物活性Tipifarnib(IND58359)抑制法尼转移酶(FTase)，IC50为0.86nM。Tipifarnib具有潜在抗肿瘤活性[1]。IC50&TargetIC50:0.86nM(FTase)体外研究TipifarnibinhibitsthegrowthofH-Ras-transformedNIH3T3cellswithanimpressiveIC50valueof1.7nM[1].TipifarnibisapotentinhibitorofTrypanosomaCruziwiththeED50of4nM[1].CombiningTipifarnibwith10nM4-OH-ICI47699inthepresenceofE2reducestheIC508-foldfrom400to50nM[2].TipifarnibinhibitsisolatedhumanfarnesyltransferaseforalaminBpeptideandfortheK-RasBpeptidewithIC50of0.86nMand7.9nM,respectively[3].Tipifarnibshowsinhibitionofcellgrowthorangiogenesis,andinductionofapoptosisinaggressiveprostatecancer(PCa)[4].TipifarnibshowsasignificantdecreaseintheconcentrationofexosomesinC4-2Bcellsbothat0.25and1ꢀμMaswellasinthePC-3cellsat0.25ꢀμMfor48ꢀhours[4].Tipifarnib(1ꢀμM)significantlyinhibitstheproteinconcentrationofAlix,nSMase2,andRab27ainC4-2Bcells[4].Tipifarnib(0.25μM)significantlyinhibitstheactivationofp-ERK(downstreameffectormoleculeoftheRas/Raf/ERKsignalingpathway)butnottotalERKinC4-2BandPC-3cellsbutnotinthenormalRWPE-1cells[4].Tipifarnib(0-250ꢀnM)causesadose-dependentdecreaseinAlix,nSMase2,andRab27ainbothC4-2BandPC-3cells,butnotintheRWPE-1cells,Tipifarnibhasthepotentialtobeapotentinhibitorofexosomebiogenesisand/orsecretion[4].体内研究CombinedtherapywithICI47699andTipifarnib(50mg/kg,p.o.)producesgreatertumorgrowthinhibitionwhencomparedwitheitherdrugalone.E2deprivationandTipifarnibincombinationresultsingreatergrowthinhibitionthaneitherE2deprivationorTipifarnibalone.ThecombinationofICI47699andTipifarnibresultsinsignificantlylowerKi-67comparedwitheitherICI47699orTipifarnibalone.TipifarnibalonealsoreducestheCTIcomparedwithcontrol.ThecombinationofICI47699andTipifarniborTipifarnibcoupledwithE2withdrawalismosteffectiveatloweringtheCTI(0.8and0.7,respectively),whichmayaccountforthedecreaseintumorvolume[2].PROTOCOL2/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemECellAssay[2]Steroid-depletedcellsareseededinto12-wellplatesatadensityofappr1×104cellsperwellorinto96-wellplatesatadensityof4,000cellsperwell,indextran-coatedcharcoalmedium.After24h,monolayersaretreatedwithE2plusinhibitorseitheraloneorincombination.The12-wellplatesaretreatedfor6dayswithdailychanges.CellnumberisthendeterminedusingaZ1Coultercounter.The96-wellplatesaretreatedwithasingledoseandleftfor96hatwhichtimecellviabilityismeasuredusing3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromideassayasdescribedpreviously.TheinteractionbetweenTipifarniband4-OH-ICI47699isanalyzedbythemedianeffectplotmethoddescribedbyChouandTalalay.Calculationofthecombinationindextookintoaccountanonfixeddrugratioandisbasedontheassumptionthattheactionofthetwodrugsismutuallynonexclusiveforthestrictdetectionofsynergism.Acombinationindex<1indicatessynergism,combinationindex=1indicatesadditivity,andacombinationindex>1indicatesantagonism.Experimentsarerepeatedthrice.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalFemaleovariectomizedNcrfoxheadnudemicearekeptundersterileconditionswithfreeaccesstofoodandAdministration[2]water.MCF-7xenograftsareinitiatedbyimplantationof2-mmdiametertumorfragmentsfromestablishedtumors.Oncetumorsreachadiameterofappr7mm,micearerandomizedtoreceivevehicle[20%w/vβ-cyclodextrin(pH2.5)forTipifarnib,50%PEG300,50%H2O+1drop1NHClper3mLforICI47699],Tipifarnib(50mg/kgtwicedaily),ICI47699(20mg/kg),oracombinationofbothTipifarnibandICI47699.TwofurthertreatmentarmsareusedtoassesstheeffectofE2withdrawal(removaloftheE2pellet)orE2withdrawalcombinedwithTipifarnib(50mg/kgtwicedaily).Alldrugsaregivenbyoralgavagedailyfor5consecutivedaysfollowedbya2-dayrestperiod,foratotalof19days.Theexperimentisdonetwicegivingsimilarresults;therefore,thegrowthdataarecombinedforstatisticalanalysis.Therearesixtumor-bearinganimalsineachgroupandalltumorsareharvestedonday19.Tumorvolumesarecalculatedusingtheformulaa×b2×π/6,whereaandbareorthogonaltumordiametersandexpressedasapercentageofthevolumeatthestartoftreatment(relativetumorvolume).OverallstatisticaldifferenceiscalculatedusingtheKruskal-WallacetestandstatisticaldifferencesbetweenindividualtreatmentarmsarecalculatedusingtheMann-Whitneytest.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•MolCell.2021Jul1;81(13):2736-2751.e8.•MolCell.2021Oct7;81(19):4076-4090.e8.•JImmunotherCancer.2022Apr;10(4):e004399.•PlantCellEnviron.2022Nov1.•MolPlantPathol.2019Sep;20(9):1264-1278.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].DevendraSPuntambekar,etal.Inhibitionoffarnesyltransferase:arationalapproachtotreatcancer?JEnzymeInhibMedChem.2007Apr;22(2):127-40.3/4MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE[2].MartinLA,etal.ThefarnesyltransferaseinhibitorR115777(tipifarnib)incombinationwithI