Vevorisertib-trihydrochloride-ARQ-751-trihydrochloride-DataSheet-生命科學(xué)試劑-MedChemExpress

Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEVevorisertibtrihydrochlorideCat.No.:HY-137458ACASNo.:1416775-08-0Synonyms:ARQ751trihydrochloride分?式:C??H??Cl?N?O分?量:696.11作?靶點(diǎn):Akt作?通路:PI3K/Akt/mTOR儲(chǔ)存?式:PleasestoretheproductundertherecommendedconditionsintheCertificateofAnalysis.BIOLOGICALACTIVITY?物活性Vevorisertib(ARQ751)trihydrochloride選擇性、變構(gòu)、pan-AKT和AKT1-E17K突變抑制劑，可有效抑制AKT的磷酸化。Vevorisertibtrihydrochloride對(duì)AKT1和AKT1-E17K的Kd值分別為1.2nM和8.6nM。Vevorisertibtrihydrochloride對(duì)AKT1、AKT2和AKT3的IC50值分別為0.55、0.81和1.3nM。Vevorisertibtrihydrochloride可?于癌癥的研究[1]。IC50&TargetAkt1Akt2Akt3Akt10.55nM(IC50)0.81nM(IC50)1.31nM(IC50)1.2nM(Kd)Akt1E17K8.6nM(Kd)體外研究Vevorisertibtrihydrochloride(0,12,33,111,333,1000nM,2hours)inhibitsphosphorylationofAKT1-E17K[1].Vevorisertibtrihydrochloride(1μMfor2hours;NIH3T3cellsaretransfectedwitheitherpcDNAAKT-WT-GFPorpcDNA-E17K-GFP)inhibitsplasmamembranetranslocationofAKT-WTandAKT1-E17Kirrespectiveofthepresenceofgrowthfactors[1].Vevorisertibtrihydrochloride(5μM)exhibites57%inhibitionoffull-lengthAKT1[1].Vevorisertibtrihydrochloride(0,0.012,0.037,0.11,0.33,1μM;2hours)showsadose-dependenteffectonmTORC1andAKTdirectsubstratesincludingPRAS40,GSK3β,FOXO,BAD,andAS160incancercelllines[1].Vevorisertibtrihydrochloridehasanti-proliferativeeffectonesophageal,breast,andheadandneckcancercells(GI50<1μM)[1].1/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEVevorisertibtrihydrochlorideexhibitsstronganti-proliferativeactivityinPIK3CAmutantcelllines[1].Vevorisertibtrihydrochloride(MK-4440)/imatinibmesylate(IM)combinationshowscellcyclearrest,andincreasescelldeathofgastrointestinalstromaltumor(GIST)cells[2].Vevorisertibtrihydrochlorideexhibitsstronganti-proliferativeactivityinPIK3CAmutantcelllines[1]:BreastCancerCellLinesGI50(nM)PIK3CAERPRHER2T47D1.05H1047R++-EFM-191.54H1047R++-MCF-72.20E545K++-BT4743.25K111N+++MDA-MB-4536.05H1047R--+WesternBlotAnalysis[1]CellLine:293Tcells(transientlytransfectedwithpcDNA-E17K-GFP)Concentration:0,12,33,111,333,1000nMIncubationTime:2hoursResult:InhibitedphosphorylationofAKT1-E17K.WesternBlotAnalysis[1]CellLine:Cancercelllines:MDA-MB453(PIK3CAH1047R;Her2amp),NCI-H1650(PTENnull),KU-19-19(AKT1-E17K&E49K;NRasQ61R)Concentration:0,0.012,0.037,0.11,0.33,1μMIncubationTime:2hoursResult:Showedadose-dependenteffectonmTORC1andAKTdirectsubstratesincludingPRAS40,GSK3β,FOXO,BAD,andAS160.體內(nèi)研究Vevorisertibtrihydrochloride(25,50and75mg/kg;p.o.;5daysdosingfollowedbya4daydosingholidayfor20days)showspotenttumorgrowthinhibitionof68,78and98%,respectively[1].Vevorisertibtrihydrochloride(5,10,20,40,80,and120mg/kg;p.o.dailyfortendays)showstumorgrowthinhibitionof29,33,50,73,83,and92%,respectively[1].VevorisertibtrihydrochloridereachsCmaxplasmaconcentrationsof≥2μM[1].Vevorisertibtrihydrochlorideisgenerallywell-toleratedatdoselevelsupto120mg/kg[1].Vevorisertibtrihydrochloride(MK-4440)/IMcombinationshowssuperiorefficacyinanIM-sensitivepreclinicalmodelofGISTcomparedwitheithersingleagent[2].AnimalModel:EndometrialPDXmousexenograftmodels(AKT1-E17Kmutationtumorfragmentssubcutaneouslyimplantedinathymicnudemice;tumorvolumeofapproximately200mm3)[1]Dosage:25,50and75mg/kgAdministration:p.o.;5daysdosingfollowedbya4daydosingholidayfor20daysResult:Showedpotenttumorgrowthinhibitionof68,78and98%,respectively.2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemEAnimalModel:AN3CAmousexenograftmodels(femaleNCrnu/numicewith250mm3tumorssize)[1]Dosage:5,10,20,40,80,and120mg/kgAdministration:p.o.;dailyfortendaysResult:Showedtumorgrowthinhibitionof29,33,50,73,83,and92%,respectively.REFERENCES[1].YuY,etal.TargetingAKT1-E17KandthePI3K/AKTPathwaywithanAllostericAKTInhibitor,ARQ092.PLoSOne.2015Oct15;10(10):e0140479.[2].KozinovaM,etal.CombinedInhibitionofAKTandKITRestoresExpressionofProgrammedCellDeath4(PDCD4)inGastrointestinalStromalTumor.Cancers(Basel).2021Jul23;13