OSI-027-ASP7486-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEOSI-027Cat.No.:HY-10423CASNo.:936890-98-1Synonyms:ASP7486分⼦式:C₂₁H₂₂N₆O₃分⼦量:406.44作⽤靶点:mTOR;Autophagy作⽤通路:PI3K/Akt/mTOR;Autophagy储存⽅式:Powder-20°C3yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:125mg/mL(307.55mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制备储备液1mM2.4604mL12.3019mL24.6039mL5mM0.4921mL2.4604mL4.9208mL10mM0.2460mL1.2302mL2.4604mL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%salineSolubility:≥2.5mg/mL(6.15mM);Clearsolution1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemE2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(6.15mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY⽣物活性OSI-027(ASP7486)⼀种有效、选择性、具有⼝服活性和ATP竞争性的mTOR激酶活性抑制剂，IC50为4nM。OSI-027抑制mTORC1和mTORC2，IC50分别为22nM和65nM。IC50&TargetmTORmTORC1mTORC2PI3K-γ4nM(IC50)22nM(IC50)65nM(IC50)0.42μM(IC50)PI3K-αDNA-PKAutophagy1.3μM(IC50)1μM(IC50)体外研究OSI-027isanATP-competitiveinhibitor,whichtargetsbothmTORC1andmTORC2withIC50sof22nMand65nM.OSI-027alsoinhibitsPI3K-α,PI3K-γandDNA-PKwithIC50sof1.3μM,0.42μMand1.0μM.OSI-027inhibitsmTORsignalingofphospho-4E-BP1withanIC50of1μM[1].体内研究EffectsonGEOcolorectalxenograftgrowthtreatedwithRapamycinorOSI-027for12daysareconsistentwithourinvitroexperiments.TreatmentwithRapamycin(20mg/kg)inhibitsphospho-S6andphospho-4E-BP1,whileAktphosphorylationisincreasedby29%.Incontrast,OSI-027(65mg/kg)inhibitsbothmTORC1andmTORC2effectors.After2hours,decreased4E-BP1,Akt,andS6phosphorylationisobservedandinhibitionofS6andAktissustainedfor24hours.TheplasmadrugconcentrationofOSI-027inverselycorrelatedwiththeseeffectsonmTORC1andmTORC2signaling.ThemedianplasmadrugconcentrationwithOSI-027is21.3μMat2hoursand14.9μMat8hours.TheinvivoefficacyofOSI-027plusSunitinibistestedinH292humanlungandOvcar-5humanovarianxenografttumors.H292tumors,treatedwithOSI-027(50mg/kg)for21dayshave61%mediantumorgrowthinhibitionforthedurationoftreatment(TGI).Sunitinib(40mg/kg)for21dayshad47%medianTGI.CombiningOSI-027withSunitinib,however,hasamedianTGIof100%with59%maximaltumorregression,astatisticallysignificantimprovementovereitheragentalone.Ovcar-5xenografttumorstreatedwithOSI-027orSunitinibhavea55%and68%medianTGI,respectively.OSI-027administeredwithSunitinibhasasignificantlybettermedianTGIof100%with38%maximaltumorregression[1].IntheRapamycin(RAPA)group,threeratsexhibitsymptomstypicalofLTx-aGVHDanddie27to35daysafterlivertransplantation(LT);theremainingfiveratsdonotdevelopLTx-aGVHDsymptomsandsurviveformorethan100days.Incontrast,sevenratsintheOSI-027groupsurviveformorethan100dayswithoutsymptomsofLTx-aGVHD,andonlyoneratexhibitsLTx-aGVHDsymptomsanddiesonday33afterLT[3].PROTOCOLKinaseAssay[1]Assaysofapanelof40otherrecombinantkinasesincludingbothproteinandlipidkinasesareperformedat100mMATPconcentrationbySelectScreenprofilingservice.AbroadpanelofkinasesistestedatasingleconcentrationofOSI-027orOXA-01(3μM)toevaluatepercentinhibitionofeachkinaseormutantvariant,2/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemEusingtheAmbitKinomeScanplatform[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.CellAssay[1]Tostudytheeffectofdrugtreatmentoncellularsignaling,Ovcar-3cellsareplatedinnormalgrowthmedium.After24hours,serumisremovedandcellsareserum-starvedovernight.Rapamycin,OSI-027andOXA-01aresolubilizedinDMSOandaddedtocellsatvaryingconcentrations.Afteratwo-hourincubationcellsaregrowthfactorstimulatedwith10ng/mLInsulinfor3to5minutes,thenrinsedwithcoldPBSandlysed[1].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.AnimalMice[1]Administration[1]Forxenograftmodels,cellsareharvested,herightflankofnu/nuCD-1miceandtumorgrowthisanalyzed.MicebearingGEOxenograftsaretreatedfor12dayswithOSI-027(65mg/kg)orvehicleandtumorscollectedat2,8,and24hours.Tumorgrowthinhibitionandregressioncalculationsareincluded.Rats[2]Specificpathogen-freefemaleLewisrats,maleBNrats,maleLew-Tg(CAG-EGFP)YsRrrcratsandmaleLew-TgYsRrrcratsareused.OrthotopicLTisundertaken.Noantibioticswereused.Freshlypreparedsplenocytes(4×108,suspendedin500μLPBS)ofLew-TgYsRrrcratsareinfusedintoeachrecipientviathedorsalpenileveinimmediatelyafterLT(within30min).LTx-aGVHDmodelratsaredividedintothreeexperimentalgroups:RAPA(1mg/kg),OSI-027(1mg/kg)orcontrol(equalquantityofvehicle)groups;treatmentsareadministeredviathevenacaudalisfromday7today15.MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.户使⽤本产品发表的科研⽂献•SciTranslMed.2018Jul18;10(450).pii:eaaq1093.•EBioMedicine.2015Nov19;2(12):1944-56.•CellSyst.2018Apr25;6(4):424-443.e7.•Cancers(Basel).2022,14(23),5854•Molecules.2020Apr23;25(8):1980.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].FalconBL,etal.ReducedVEGFproduction,angiogenesis,andvascularregrowthcontributetotheantitumorpropertiesofdualmTORC1/mTORC2inhibitors.CancerRes.2011Mar1;71(5):1573-83.[2].ZhiX,etal.OSI-027modulatesacutegraft-versus-hostdiseaseafterlivertransplantationinaratmodel.LiverTranspl