BMS-690514-DataSheet-生命科学试剂-MedChemExpress

Hotline:400-820-3792Inhibitors•ScreeningLibraries•Proteinswww.MedChemEBMS-690514Cat.No.:HY-10333CASNo.:859853-30-8分⼦式:C₁₉H₂₄N₆O₂分⼦量:368.43作⽤靶点:EGFR;VEGFR作⽤通路:JAK/STATSignaling;ProteinTyrosineKinase/RTK储存⽅式:Powder-20°C3years4°C2yearsInsolvent-80°C6months-20°C1month溶解性数据体外实验DMSO:≥25mg/mL(67.86mM)*"≥"meanssoluble,butsaturationunknown.MassSolvent1mg5mg10mgConcentration制备储备液1mM2.7142mL13.5711mL27.1422mL5mM0.5428mL2.7142mL5.4284mL10mM0.2714mL1.3571mL2.7142mL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%saline1/3MasterofBioactiveMolecules—您⾝边的抑制剂⼤师www.MedChemESolubility:≥2.5mg/mL(6.79mM);Clearsolution2.请依序添加每种溶剂：10%DMSO>>90%(20%SBE-β-CDinsaline)Solubility:≥2.5mg/mL(6.79mM);Clearsolution3.请依序添加每种溶剂：10%DMSO>>90%cornoilSolubility:≥2.5mg/mL(6.79mM);ClearsolutionBIOLOGICALACTIVITY⽣物活性BMS-690514有效，有⼝服活性的EGFR和VEGFR的有效抑制剂，对于EGFR，HER2和HER4的IC50值分别为5，9和60nM。IC50&TargetEGFRHER2HER45nM(IC50)20nM(IC50)60nM(IC50)体外研究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].体内研究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—您⾝边的抑制剂⼤师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.户使⽤本产品发表的科研⽂献•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