Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEOSI-027Cat.No.:HY-10423CASNo.:936890-98-1Synonyms:ASP7486分?式:C??H??N?O?分?量:406.44作?靶點(diǎn):mTOR;Autophagy作?通路:PI3K/Akt/mTOR;Autophagy儲(chǔ)存?式:Powder-20°C3yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實(shí)驗(yàn)DMSO:125mg/mL(307.55mM;Needultrasonic)MassSolvent1mg5mg10mgConcentration制備儲(chǔ)備液1mM2.4604mL12.3019mL24.6039mL5mM0.4921mL2.4604mL4.9208mL10mM0.2460mL1.2302mL2.4604mL請(qǐng)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(chǔ)備液；?旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存?式和期限：-80°C,6months;-20°C,1month。-80°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?，-20°C儲(chǔ)存時(shí)，請(qǐng)?jiān)?個(gè)?內(nèi)使?。體內(nèi)實(shí)驗(yàn)請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥?式選擇適當(dāng)?shù)娜芙?案。以下溶解?案都請(qǐng)先按照InVitro?式配制澄的儲(chǔ)備液，再依次添加助溶劑：(為保證實(shí)驗(yàn)結(jié)果的可靠性，澄的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的?作液，建議您現(xiàn)?現(xiàn)配，當(dāng)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(guò)程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過(guò)加熱和/或超聲的?式助溶)1.請(qǐng)依序添加每種溶劑：10%DMSO>>40%PEG300>>5%Tween-80>>45%salineSolubility:≥2.5mg/mL(6.15mM);Clearsolution1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemE2.請(qǐng)依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:2.5mg/mL(6.15mM);Suspendedsolution;NeedultrasonicBIOLOGICALACTIVITY?物活性O(shè)SI-027(ASP7486)?種有效、選擇性、具有?服活性和ATP競(jìng)爭(zhēng)性的mTOR激酶活性抑制劑，IC50為4nM。OSI-027抑制mTORC1和mTORC2，IC50分別為22nM和65nM。IC50&TargetmTORmTORC1mTORC2PI3K-γ4nM(IC50)22nM(IC50)65nM(IC50)0.42μM(IC50)PI3K-αDNA-PKAutophagy1.3μM(IC50)1μM(IC50)體外研究OSI-027isanATP-competitiveinhibitor,whichtargetsbothmTORC1andmTORC2withIC50sof22nMand65nM.OSI-027alsoinhibitsPI3K-α,PI3K-γandDNA-PKwithIC50sof1.3μM,0.42μMand1.0μM.OSI-027inhibitsmTORsignalingofphospho-4E-BP1withanIC50of1μM[1].體內(nèi)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?邊的抑制劑?師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.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?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