Sonidegib-Erismodegib-DataSheet-生命科學試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemESonidegibCat.No.:HY-16582ACASNo.:956697-53-3Synonyms:Erismodegib;LDE225;NVP-LDE225分?式:C??H??F?N?O?分?量:485.5作?靶點:Smo作?通路:StemCell/Wnt儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:50mg/mL(102.99mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.0597mL10.2987mL20.5973mL5mM0.4119mL2.0597mL4.1195mL10mM0.2060mL1.0299mL2.0597mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；?旦配成溶液，請分裝保存，避免反復凍融造成的產(chǎn)品失效。儲備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲存時，請在6個?內(nèi)使?，-20°C儲存時，請在1個?內(nèi)使?。體內(nèi)實驗請根據(jù)您的實驗動物和給藥?式選擇適當?shù)娜芙?案。以下溶解?案都請先按照InVitro?式配制澄的儲備液，再依次添加助溶劑：(為保證實驗結(jié)果的可靠性，澄的儲備液可以根據(jù)儲存條件，適當保存；體內(nèi)實驗的?作液，建議您現(xiàn)?現(xiàn)配，當天使?；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.請依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%saline1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemESolubility:≥2.5mg/mL(5.15mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(5.15mM);Suspendedsolution;Needultrasonic3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(5.15mM);ClearsolutionBIOLOGICALACTIVITY?物活性Sonidegib(Erismodegib)?種有效，選擇性的Smo拮抗劑，抑制?和?Smo的IC50分別為1.3nM和2.5nM[1]。IC50&TargetIC50:1.3nM(mSmo),2.5nM(hSmo)[1]體外研究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].體內(nèi)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?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻?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