Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemETipifarnibCat.No.:HY-10502CASNo.:192185-72-1Synonyms:IND58359;R115777分?式:C??H??Cl?N?O分?量:489.4作?靶點(diǎn):FarnesylTransferase作?通路:MetabolicEnzyme/Protease儲(chǔ)存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:14.29mg/mL(29.20mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.0433mL10.2166mL20.4332mL5mM0.4087mL2.0433mL4.0866mL10mM0.2043mL1.0217mL2.0433mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)天使?；以下溶劑前顯?的百分?指該溶劑在您配制終溶液中的體積占?；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/4MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥1.43mg/mL(2.92mM);Clearsolution2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:1.43mg/mL(2.92mM);Suspendedsolution;Needultrasonic3.請(qǐng)依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥1.43mg/mL(2.92mM);Clearsolution4.請(qǐng)依序添加每種溶劑：20%HP-β-CD/10mMcitratepH2.0Solubility:10mg/mL(20.43mM);Clearsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性Tipifarnib(IND58359)抑制法尼轉(zhuǎn)移酶(FTase)，IC50為0.86nM。Tipifarnib具有潛在抗腫瘤活性[1]。IC50&TargetIC50:0.86nM(FTase)體外研究TipifarnibinhibitsthegrowthofH-Ras-transformedNIH3T3cellswithanimpressiveIC50valueof1.7nM[1].TipifarnibisapotentinhibitorofTrypanosomaCruziwiththeED50of4nM[1].CombiningTipifarnibwith10nM4-OH-ICI47699inthepresenceofE2reducestheIC508-foldfrom400to50nM[2].TipifarnibinhibitsisolatedhumanfarnesyltransferaseforalaminBpeptideandfortheK-RasBpeptidewithIC50of0.86nMand7.9nM,respectively[3].Tipifarnibshowsinhibitionofcellgrowthorangiogenesis,andinductionofapoptosisinaggressiveprostatecancer(PCa)[4].TipifarnibshowsasignificantdecreaseintheconcentrationofexosomesinC4-2Bcellsbothat0.25and1?μMaswellasinthePC-3cellsat0.25?μMfor48?hours[4].Tipifarnib(1?μM)significantlyinhibitstheproteinconcentrationofAlix,nSMase2,andRab27ainC4-2Bcells[4].Tipifarnib(0.25μM)significantlyinhibitstheactivationofp-ERK(downstreameffectormoleculeoftheRas/Raf/ERKsignalingpathway)butnottotalERKinC4-2BandPC-3cellsbutnotinthenormalRWPE-1cells[4].Tipifarnib(0-250?nM)causesadose-dependentdecreaseinAlix,nSMase2,andRab27ainbothC4-2BandPC-3cells,butnotintheRWPE-1cells,Tipifarnibhasthepotentialtobeapotentinhibitorofexosomebiogenesisand/orsecretion[4].體內(nèi)研究CombinedtherapywithICI47699andTipifarnib(50mg/kg,p.o.)producesgreatertumorgrowthinhibitionwhencomparedwitheitherdrugalone.E2deprivationandTipifarnibincombinationresultsingreatergrowthinhibitionthaneitherE2deprivationorTipifarnibalone.ThecombinationofICI47699andTipifarnibresultsinsignificantlylowerKi-67comparedwitheitherICI47699orTipifarnibalone.TipifarnibalonealsoreducestheCTIcomparedwithcontrol.ThecombinationofICI47699andTipifarniborTipifarnibcoupledwithE2withdrawalismosteffectiveatloweringtheCTI(0.8and0.7,respectively),whichmayaccountforthedecreaseintumorvolume[2].PROTOCOL2/4MasterofBioactiveMolecules—您?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?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?邊的抑制劑?師www.MedChemE[2].MartinLA,etal.ThefarnesyltransferaseinhibitorR115777(tipifarnib)incombinationwithI