Hotline:400-820-3792Inhibitors?ScreeningLibraries?Proteinswww.MedChemEBMS-690514Cat.No.:HY-10333CASNo.:859853-30-8分?式:C??H??N?O?分?量:368.43作?靶點:EGFR;VEGFR作?通路:JAK/STATSignaling;ProteinTyrosineKinase/RTK儲存?式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性數(shù)據(jù)體外實驗DMSO:≥25mg/mL(67.86mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制備儲備液1mM2.7142mL13.5711mL27.1422mL5mM0.5428mL2.7142mL5.4284mL10mM0.2714mL1.3571mL2.7142mL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(fù)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(dāng)?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(dāng)保存；體內(nèi)實驗的?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(6.79mM);Clearsolution2.請依序添加每種溶劑：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(6.79mM);Clearsolution3.請依序添加每種溶劑：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.79mM);ClearsolutionBIOLOGICALACTIVITY?物活性BMS-690514有效，有?服活性的EGFR和VEGFR的有效抑制劑，對于EGFR，HER2和HER4的IC50值分別為5，9和60nM。IC50&TargetEGFRHER2HER45nM(IC50)20nM(IC50)60nM(IC50)體外研究BMS-690514targetsseveralcriticalsignalingpathways:humanepidermalgrowthfactorreceptor(HER)/ErbB,angiogenesissignalingthroughVEGFR2,lymphangiogenesisthroughVEGFR3,andalsoshowsactivityagainstVEGFR1,Flt-3,andLck.PermeabilityofBMS-690514inCaco-2cellsisintheintermediaterangewithamoderatepotentialtobeaP-gpsubstrate[2].BMS-690514inhibitsmembersoftheVEGFRfamilywithIC50valuesintherangeof25to50nM.Non–smallcelllungtumorcellswithexon19deletion(HCC4006,HCC827,andPC9)arehighlysensitivetoBMS-690514,whichinhibitstheirproliferationwithIC50valuesof2to35nM.TumorcelllineswithEGFRgeneamplification(DiFi,NCI-H2073,A431)arealsohighlysensitivetoinhibitionbyBMS-690514.TumorcelllinesthataredependentonHER2signalingarealsofoundtobehighlysensitivetoBMS-690514.BreastandgastrictumorcelllinesthathaveHER2geneamplification(N87,SNU-216,AU565,BT474,KPL4,andHCC202)areinhibitedwithIC50valuesof20to60nM[1].體內(nèi)研究BMS-690514hasbeenshowntobeefficaciousinabroadspectrumoftumorxenografts.Atdosesthatareefficaciousandwelltoleratedintheanimalmodels,BMS-690514inhibitstumorcellproliferationandtumorbloodflow[1].TheoralbioavailabilityofBMS-690514is78%inmice,100%inrats,8%inmonkeys,and29%indogs.BMS-690514isabletocrosstheblood–brainbarrierwithabrain-to-plasmaratioof1.ThepreclinicalADMEpropertiesofBMS-690514suggestgoodoralbioavailabilityinhumansandmetabolismbymultiplepathwaysincludingoxidationandglucuronidation[2].PROTOCOLAnimalRats:BMS-690514isadministeredtomaleSprague–Dawleyratsasa10mininfusionintraarterially(IA)(1Administration[2]mg/kg)ororallybygavage(10mg/kg).Vehiclesusedfordosingare:IA,10mMacetatebuffer(pH5.0,1mL/kg)andPO,PEG400/10mMacetatebuffer(pH5.0,2mL/kg)(10:90).Serialplasmasamplesareobtainedpredoseandat0.17(or0.25forPO),0.5,0.75,1,2,4,6,8,12,and24hpostdose.Ratsarefastedovernightandfed4hpostdose.ThebrainuptakeofBMS-690514isinvestigatedafterthelastdoseina2-weektoxicologystudy(3,10,and30mg/kg/day).Brainsamplesareweighedandhomogenizedin3volumesofice-chilledwater.ConcentrationsofBMS-690514inplasmaandbrainhomogenatesaredeterminedby2/3MasterofBioactiveMolecules—您?邊的抑制劑?師www.MedChemELC/MS/MS[2].Mice:ThepharmacokineticsofBMS-690514isinvestigatedinmalebalb-cmice.Atotalof18micearedividedintotwogroupstoreceiveBMS-690514asasingledoseof1mg/kgIVbolusor5mg/kgorallybygavage.ThevehicleusedforbothIV(0.1mL/mouse)andPO(0.2mL/mouse)doseisTween-80/PG/water(10:40:50).SerumconcentrationsofBMS-690514aremeasuredat0.05(or0.25forPO),0.5,1,3,6,8,and24hpostdose.Themicearefastedovernightandfed6hafterdosing.Threebloodsamplesaretakenfromeachmousebyretro-orbitalbleedingandtherearethreemicepertimepoint.Atthe24htimepointonlyonesampleistakenfromeachofthethreemice.Compositeserumconcentration–timeprofilesareconstructedforpharmacokineticanalysis[2].MCEhasnotindependentlyconfirmedtheaccuracyofthesemethods.Theyareforreferenceonly.戶使?本產(chǎn)品發(fā)表的科研?獻(xiàn)?Science.2017Dec1;358(6367):eaan4368.?TechnicalUniversityofMunich.24.01.2018.Seemorecustomervalidationsonwww.MedChemEREFERENCES[1].WongTW,etal.AntitumorandantiangiogenicactivitiesofBMS-690514,aninhibitorofhumanEGFandVEGFreceptorkinasefamilies.ClinCancerRes.2011Jun15;17(12):4031-41.[2].MaratheP,etal.PreclinicalpharmacokineticsandinvitrometabolismofBMS-690514,apotentinhibitorofEGF