Medchemexpress/SB-431542/HY-10431/50mg

SB-431542isapotentandselectiveinhibitorofALK5andALK4withIC₅₀valuesof94nMand14nM,respectivelly,andisalsoaninhibitorofTGF-βReceptor.

IC50:94nM(ALK5),140nM(ALK4)

SB-431542(1μM)significantlyreducestheTGF-β-inducednuclearaccumulationofSmadproteinsinA498cells.SB-431542inhibitsTGF-β1-inducedcollagenIα1andPAI-1mRNAwithIC₅₀valuesof60and50nM,respectively.Inaddition,SB-431542inhibitsTGF-β1-inducedfibronectinmRNAandproteinwithIC₅₀valuesof62and22nM,respectively^[1].SB-431542(10μM)isaselectiveinhibitorofendogenousactivinandTGF-βsignalingbuthasnoeffectonBMPsignalinginNIH3T3cells^[2].TRKI,SB-431542,inhibitsTGF-beta-inducedtranscription,geneexpression,apoptosis,andgrowthsuppression.SB-431542attenuatesthetumor-promotingeffectsofTGF-beta,includingTGF-beta-inducedEMT,cellmotility,migrationandinvasion,andvascularendothelialgrowthfactorsecretioninhumancancercelllines.SB-431542inducesanchorageindependentgrowthofcellsthataregrowth-inhibitedbyTGF-beta,whereasitreducescolonyformationbycellsthataregrowth-promotedbyTGF-beta^[3].SB-431542(0.3μM)inhibitscellproliferationinducedbyTGF-βinMG63cells^[4].

SB-431542(10mg/kg,i.p.)decreaseslungmetastasisbutdoesnotsignificantlyaltergrowthoftheprimarytumor4T1xenograft^[5].

• [1].N.J.Laping,etal.InhibitionofTransformingGrowthFactor(TGF)-β1-InducedExtracellularMatrixwithaNovelInhibitoroftheTGF-βTypeIReceptorKinaseActivity:SB-431542.

  [2].InmanGJ,etal.SB-431542isapotentandspecificinhibitoroftransforminggrowthfactor-betasuperfamilytypeIactivinreceptor-likekinase(ALK)receptorsALK4,ALK5,andALK7.MolPharmacol,2002,62(1),65-74.

  [3].HalderSK,etal.AspecificinhibitorofTGF-betareceptorkinase,SB-431542,asapotentantitumoragentforhumancancers.Neoplasia,2005,7(5),509-521.

  [4].MatsuyamaS,etal.SB-431542andGleevecinhibittransforminggrowthfactor-beta-inducedproliferationofhumanosteosarcomacells.CancerRes,2003,63(22),7791-7798.

  [5].SatoM,etal.DifferentialProteomeAnalysisIdentifiesTGF-β-RelatedPro-MetastaticProteinsina4T1MurineBreastCancerModel.PLoSOne.2015May18;10(5):e0126483.

Atotalof100,000cellsfromeachpoolofA549andHT29areseededintoeachwellof12-wellplate.Cellsareculturedinmediacontaining0.2%FBSfor18hours,andthentreatedwith5ng/mLTGF-β1inthepresenceofSB-431542(10µM)in0.5mLofmediafor24hours.OnehundredμLsofeachsupernatantmediaisusedforVEGFassayaccordingtothemanufacturer"sinstruction.ForTGF-β1ELISA,100,000cellsfromeachpoolofA549,VMRC-LCD,andHT29areseededintoeachwellof12-wellplatesandserum-starvedfor20hours.CellsarethentreatedwithSB-431542in0.5mLofserum-freeRPMImediafor24hours.OnehundredμLsofeachsupernatantmediaisactivatedandusedforTGF-β1assayaccordingtothemanufacturer"sinstruction.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

SB-431542isdissolvedataconcentrationof10mMinDMSO.

A498cellsareseededat5,000to10,000cells/wellin96-wellplates.Thecellsareserum-deprivedfor24handthentreatedwithSB-431542for48htoassessthecellulartoxicity.CellviABIlityisdeterminedbyincubatingcellsfor4hwithXTTlabelingandelectroncouplingreagentaccordingtothemanufacturer"sdirections.Livecellswithactivemitochondriaproduceanorange-coloredproduct,formazan,whichisdetectedusingaplatereaderatbetween A 450nm andA 500nm withareferencewavelengthgreaterthan600nm.Theabsorbancevaluescorrelatewiththenumberofviablecells.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

SB-431542isformulatedin20%DMSO/80%cornoil.

Tenthousand4T1cellsareinjectedsubcutaneouslyintothesecondmammaryfatpadof6-week-oldBalb/cfemalemice.Tumorsaremeasuredtwiceweekly,andvolumeiscalculatedusingthefollowingformula:Volume=width²×length×0.52.Micearerandomlyassignedtotwotreatmentgroups:control,n=14(20%DMSO/80%cornoil);SB-431542-treated,n=15(10mg/kgbodyweightin20%DMSO/80%cornoil,administeredintraperitoneallythreetimesperweekstartingonedayaftertumorcellinoculation.Primarytumorsareresectedwhenthevolumeatday10post-injectionof4T1cells.Allmicearemonitoreddailyandeuthanizedafter4weeks.Themetastasesaredissectedtosnap-freezeforfurtheranalysis.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.

• [1].N.J.Laping,etal.InhibitionofTransformingGrowthFactor(TGF)-β1-InducedExtracellularMatrixwithaNovelInhibitoroftheTGF-βTypeIReceptorKinaseActivity:SB-431542.

  [2].InmanGJ,etal.SB-431542isapotentandspecificinhibitoroftransforminggrowthfactor-betasuperfamilytypeIactivinreceptor-likekinase(ALK)receptorsALK4,ALK5,andALK7.MolPharmacol,2002,62(1),65-74.

  [3].HalderSK,etal.AspecificinhibitorofTGF-betareceptorkinase,SB-431542,asapotentantitumoragentforhumancancers.Neoplasia,2005,7(5),509-521.

  [4].MatsuyamaS,etal.SB-431542andGleevecinhibittransforminggrowthfactor-beta-inducedproliferationofhumanosteosarcomacells.CancerRes,2003,63(22),7791-7798.

  [5].SatoM,etal.DifferentialProteomeAnalysisIdentifiesTGF-β-RelatedPro-MetastaticProteinsina4T1MurineBreastCancerModel.PLoSOne.2015May18;10(5):e0126483.

384.39

C₂₂H₁₆N₄O₃

301836-41-9

RoomtemperatureincontinentalUS;mayvaryelsewhere

DMSO:≥40mg/mL;Ethanol:11.17mg/mL(Needultrasonicandwarming)

*"<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">