Sonidegib-Erismodegib-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemESonidegibCat.No.:HY-16582ACASNo.:956697-53-3Synonyms:Erismodegib;LDE225;NVP-LDE225分⼦式:C₂₆H₂₆F₃N₃O₃分⼦量:485.5作⽤靶点:Smo作⽤通路:StemCell/Wnt储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:50mg/mL(102.99mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.0597mL10.2987mL20.5973mL5mM0.4119mL2.0597mL4.1195mL10mM0.2060mL1.0299mL2.0597mL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%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.5mg/mL(5.15mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(5.15mM);Suspendedsolution;Needultrasonic3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.15mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性Sonidegib(Erismodegib)⼀种有效，选择性的Smo拮抗剂，抑制⿏和⼈Smo的IC50分别为1.3nM和2.5nM[1]。IC50&TargetIC50:1.3nM(mSmo),2.5nM(hSmo)[1]体外研究TheIC50valuesforSonidegib(NVP-LDE225)forthemajorhumanCYP450drugmetabolizingenzymesisgreaterthan10μM[1].Sonidegib(LDE225),asmallmolecule,clinicallyinvestigatedSMOinhibitor,usedaloneandincombinationwithNilotinib,inhibitstheHhpathwayinCD34+chronicphase(CP)-chronicmyeloidleukaemia(CML)cells,reducingthenumberandself-renewalcapacityofCMLleukaemiastemcell(LSC).SonidegibinteractsdirectlywithSMO,inasimilarfashiontocyclopamine,toreduceexpressionofdownstreamHhsignalingtargets.PrimaryCD34+CP-CMLcellsareculturedinserumfreemedia(SFM)±Sonidegibfor6,24and72hours(h).At72h,whilethereisvariabilitybetweenthebiologicalsamples,GLI1issignificantlydownregulatedfollowingexposuretoSonidegib(10nM;0.78-foldand100nM;0.73-fold,respectively(p[2].体内研究Sonidegib(NVP-LDE225)isaweakbasewithameasuredpKaof4.2andexhibitsrelativelypooraqueoussolubility.InthesubcutaneousPtch+/-p53-/-medulloblastomaallograftmousemodel,Sonidegibdemonstratesdose-relatedantitumoractivityafter10daysoforaladministrationofasuspensionofthediphosphatesalt.Atadoseof5mg/kg/dayqd,Sonidegibsignificantlyinhibitstumorgrowth,correspondingtoaT/Cvalueof33%(p[1].Bonemarrowcellsandspleencellsfromasubsetoftreatedmicearetransplantedintosecondaryrecipientmice.Transplantationofeitherbonemarrow(BM)orspleencellsfrommicetreatedwithSonidegib(LDE225)+Nilotinibresultsinreducedwhitecellcount(WCC)andreducesleukaemiadevelopmentinsecondaryrecipientscomparedtoSonidegiborNilotinibalone[2].PROTOCOLCellAssay[2]CD34+CP-CMLcellsareseededinSFMalone±Sonidegib±Nilotinibandculturedfor24-72hpriortoassessment.ProliferationismeasuredusingcolorimetricassessmentofBrDUincorporation.ProportionofviablecellsversusthoseinearlyandlateapoptosisisassessedbyflowcytometryusingannexinV-FITCand7-amino-actinomycinD(7-AAD,Via-Probesolution).CellcyclestatusisassessedusingKi67(FITC)expressionand7-AADincorporation.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[2]2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEAdministration[2]ThetransgenicEGFP+/SCLtTA/TRE-BCR-ABLmousemodelisusedtoinvestigatetheeffectofSonidegibtreatmentonCMLLSCinvivo.Scl-tTa-BCR-ABLmiceintheFVB/NbackgroundarecrossedwithtransgenicGFP-expressingmice.Bonemarrowcellsareobtained4weekspostinduction,GFP+cellsareselectedbyflowcytometryandtransplantedbytailveininjection(106cells/mouse)intowild-typeFVB/Nrecipientmice,irradiatedat900cGy,generatingalargecohortofmicewithsimilartimeofonsetofleukemia.Bloodsamplesobtained4weeksposttransplantationconfirmedaneutrophilicleukocytosisinrecipientmice.MicearetreatedwithNilotinib(50mg/kgbygavage,daily),Sonidegib(80mg/kgbygavage,daily),Sonidegib+Nilotinib,orwithvehiclealone(control).After3weeksoftreatment,animalsareeuthanisedandmarrowcontentoffemursandtibiae,spleencellsandbloodobtained.Totalwhitecellcount(WCC),GFP-expressingWCC,myeloidcells,andGFP+progenitorsandstemcellsaremeasuredbyflowcytometry.Survivalisassessedinasubsetofmicefor120dpostdiscontinuationoftreatment.SpleenandBMcellsfromasubsetofmiceineacharmarepooledand5×106cells/mouse(8mice/condition)aretransplantedintowild-typeFVB/Nrecipientmiceirradiatedat900cGy.Engraftmentismonitoredbydrawingperipheralblood(PB)every4weeks.ThepercentageofGFP+cellsinPBisanalyzedbyflowcytometry.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•NatMed.2018Nov;24(11):1752-1761.•JGenetGenomics.2018May20;45(5):237-246.•Patent.US20180263995A1.•CellPhysiolBiochem.2018;47(4):1352-1364.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].PanS,etal.DiscoveryofNVP-LDE225,aPotentandSelectiveSmoothenedAntagonist.ACSMedChemLett.2010Mar16;1(3):130-4.[2].IrvineDA,etal.DeregulatedhedgehogpathwaysignalingisinhibitedbythesmoothenedantagonistLDE225(Sonid