• Tandutinib(alsoknownasMLN518orCT53518)isanorallyactiveinhibitorofFms-liketyrosinekinase3(FLT3)kinase,PDGFRβandc-Kit.ItinhibitsFLT3phosphorylation,downstreamsignalingandtumorgrowthinvitroandinanimalmodels.Cheng,Y.andPaz,K."Tandutinib,anoral,small-moleculeinhibitorofFLT3forthetreatmentofAMLandothercancerindications."IDrugs11:46-56(2008).
• ThesensitivityofcelllinestotandutinibisincreasedbyFLT3siRNA-induceddown-regulationofFLT3.Walters,D.K.,etal."RNAi-induceddown-regulationofFLT3expressioninAMLcelllinesincreasessensitivitytoMLN518."Blood105:2952-2954(2005).
• InhumanFLT3-ITD-positiveacutemyelogenousleukemia(AML)celllines,tandutinibinducedapoptosisandinhibitedFLT3-ITDphosphorylation,cellularproliferation,andsignalingthroughtheMAPkinaseandPI3kinasepathways.InBa/F3cellsexpressingdifferentFLT3-ITDmutants,tandutinibalsodemonstratedinhibitionofIL-3-independentcellgrowthandFLT3-ITDautophosphorylation,withanIC50of10-100nM.TandutinibwasapotentinhibitorofFLT3-ITD-induceddiseaseinamurinemodel.Kelly,L.M.,etal."CT53518,anovelselectiveFLT3antagoNISTforthetreatmentofacutemyelogenousleukemia(AML)."CancerCell1:421-432(2002).
• TandutinibinhibitsthegrowthofblastcoloniesfromFLT3ITD-positivepatientswithacutemyelocyticleukemia(AML)moreeffectivelythanforblastcoloniesfromITD-negativeAMLpatients,atconcentrationsthatdonotsignificantlyblockcolonyformationofnormalhumanProgenitorcells.TandutinibhasmoderatetoxicitytowardnormalhematopoiesisatconcentrationsthatareusedintreatingFLT3ITD-positiveleukemiainmice.Griswold,I.J.,etal."EffectsofMLN518,adualFLT3andKITinhibitor,onnormalandmalignanthematopoiesis."Blood104:2912-2918(2004).
• TandutinibinhibitedFLT3autophosphorylationandphosphorylationofSTAT5andERKinFLT3-ITD-transformedBa/F3cells(IC50=500nM).However,therewasabroadspectrumofsensitivityamongthe8activationloopmutants(IC50=500nM-10µM)fortheinhibitionofphosphorylationofFLT3,STAT5,andERK.TherelativecellularsensitivityofthemutantstotandutinibforproliferationofFLT3-transformedBa/F3cellscorrelatedwithIC50sinthebiochemicalassays,indicatingthatcertainactivationloopmutationsinFLT3conferresistancetotandutinib.Clark,J.J.,etal."VariablesensitivityofFLT3activationloopmutationstothesmallmoleculetyrosinekinaseinhibitorMLN518."Blood104:2867-2872(2004).
• Soldforlaboratoryormanufacturingpurposesonly;notforhuman,medical,veterinary,food,orhouseholduse.
• ThisproductisofferedforR&Duseinaccordancewith(i)35USC271(e)+A13(1)intheU.S.;(ii)Section69.1ofJapanesePatentLawinJapan;(iii)Section11,No.2oftheGermanPatentActof1981inGermany;(iv)Section60,Paragraph5boftheU.K.PatentsActof1977intheU.K.;(v)Sections55.2(1)and55.2(6)andothercommonlawexemptionsofCanADIanpatentlaw;(vi)Section68BofthePatentsActof1953inNewZealandtogetherwiththeamendmentofsamebytheStatutesAmendmentBillof2002;(vii)suchrelatedlegislationand/orcaselawasmaybeorbecomeapplicableintheaforementionedcountries;and(viii)suchsimilarlawsandrulesasmayapplyinvariousothercountries.
• Notavailableinsomecountries;notavailabletosomeinstitutions;notavailableforsomeuses.

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