Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEToceranibphosphateCat.No.:HY-10330ACASNo.:874819-74-6Synonyms:SU11654phosphate;PHA291639Ephosphate分?式:C??H??FN?O?P分?量:494.45作?靶點(diǎn):PDGFR;VEGFR;c-Kit作?通路:ProteinTyrosineKinase/RTK儲(chǔ)存?式:4°C,sealedstorage,awayfrommoisture*Insolvent:-80°C,6months;-20°C,1month(sealed

storage,awayfrommoisture)溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:2.46mg/mL(4.98mM;Needultrasonicandwarming)H2O:<0.1mg/mL(insoluble)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.0224mL10.1122mL20.2245mL5mM---------10mM---------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(sealedstorage,awayfrommoisture)。-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?。BIOLOGICALACTIVITY?物活性Toceranibphosphate(SU11654phosphate)?種具有?服活性的酪氨酸激酶(RTK)受體抑制劑，能有效抑制PDGFR，VEGFR，Kit，抑制PDGFRβ和Flk-1/KDR的Ki值分別為5nM和6nM。Toceranibphosphate具有抗腫瘤和抗?管?成活性，可?于?肥?細(xì)胞腫瘤的研究[1][2]。1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEIC50&TargetPDGFRβFlk-15nM(Ki)6nM(Ki)體外研究Toceranibphosphate(PHA291639phosphate)isaselectiveinhibitorofthetyrosinekinaseactivityofseveralmembersofthesplitkinaseRTKfamily,includingPDGFRandFlk-1/KDR,withKisof5and6nM,respectively[1].ToexploremechanismsofacquiredToceranib(TOC)resistanceincanineMCT,threeresistantsublinesaregeneratedfromtheToceranib-sensitiveexon11ITDc-kitmutantC2celllinedesignatedTR1,TR2,andTR3.GrowthoftheparentalC2cellsisinhibitedbyToceranibinadose-dependentmannerwithanIC50of50>?1,000nM).SensitivitytothreeotherKITRTKinhibitorsissimilartotheobservedresistancetoToceranib.Theparentallineaswellasallthreesublinesretainssensitivitytothecytotoxicagentsvinblastine(VBL)andCCNU.Following72hrcultureinthepresenceofincreasingconcentrationsofToceranib,treatmentna?ve,parentalC2cellsdetachfromthecultureflaskandbecomerounded,shrunken,andclumpedwithincreasedexposuretoToceranib.Incontrast,Toceranib-inducedmorphologicdifferencesarenotidentifiedintheresistantsublines[2].體內(nèi)研究AdministrationofToceranibphosphate(PHA291639phosphate)significantlydecreasesthenumberandpercentageofTregintheperipheralbloodofdogswithcancer.DogsreceivingToceranibphosphate(PHA291639phosphate)andcyclophosphamide(CYC)demonstrateasignificantincreaseinserumconcentrationsofIFN-γ,whichisinverselycorrelatedwithTregnumbersafter6weeksofcombinationtreatment[3].PROTOCOLCellAssay[2]Thec-kitmutantcanineC2mastocytomacellline,derivedfromaspontaneouslyoccurringcutaneousmastcelltumors(MCTs),isusedastheparentalcellline.CellsarepropagatedinRPMI1640supplementedwith2mML-glutamine,10%FBS,100g/mLStreptomycin,and100U/mLPenicillinina37°Cincubatorunderahumidifiedatmosphereof5%CO2.Toceranib-resistantC2cellsareselectedbygrowingC2cellsinconcentrationsofToceranibrangingfrom0.02uMto0.3uMandincreasingin0.025-0.05uMincrements.Threeindependent,Toceranib-resistantsublinesareestablishedoveraperiodof7months[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalDogs[3]Administration[3]Fifteenclient-owneddogswithadvancedtumorsareused.DogsreceiveToceranibat2.75mg/kgonceeveryotherday.After2weeks,oralcyclophosphamide(CYC)isaddedat15mg/m2daily.NumbersofTregandlymphocytesubsetsaremeasuredinbloodbyflowcytometryduringthe8-weekstudyperiod.SerumconcentrationsofIFN-γaremeasuredbyELISA.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.REFERENCES[1].LondonCA,etal.PhaseIdose-escalatingstudyofSU11654,asmallmoleculereceptortyrosinekinaseinhibitor,indogswithspontaneousmalignancies.ClinCancerRes.2003Jul;9(7):2755-68.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE[2].HalseyCH,etal.Developmentofaninvitromodelofacquiredresistancetotoceranibphosphate(Palladia?)incaninemastcelltumor.BMCVetRes.2014May6;10:105.[3].MitchellL,etal.Clinicalandimmunomodulatoryeffectsoftoceranibcombinedwithlow-dosecyclophosphamideindogswithcancer.JVetInternMed.2012Mar-Apr;26(2):355-62.[4].LondonC,MathieT,StingleN,etal.Preliminaryevidenceforbiologicactivityoftoceranibphosphate(Palladia(?))insolidtumours.VetCompOncol.