| BMS-817378Potent ATP competitive inhibitor of Met/VEGFR2 |

Sample solution is provided at 25 µL, 10mM.
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Cell Stem Cell.2017 Nov 20. pii: S1934-5909(17)30375-2.Quality Control & MSDS
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- Purity = 98.00%
- COA (Certificate Of Analysis)
- MSDS (Material Safety Data Sheet)
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Chemical structure


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| Cas No. | 1174161-69-3 | SDF | Download SDF |
| Chemical Name | (Z)-N-(4-((3-chloro-2-imino-1,2-dihydropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1-((phosphonooxy)methyl)-1,4-dihydropyridine-3-carbimidic acid | ||
| Canonical SMILES | ClC1=C(OC2=C(F)C=C(/N=C(O)/C3=CN(COP(O)(O)=O)C=C(C3=O)C4=CC=C(F)C=C4)C=C2)C=CNC1=N | ||
| Formula | C24H18ClF2N4O7P | M.Wt | 578.85 |
| Solubility | Soluble in DMSO | Storage | Store at -20°C |
| Shipping Condition | Evaluation sample solution : ship with blue ice.All other available size:ship with RT , or blue ice upon request | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
Description:
IC50: 1.7 nM/15 nM for Met/VEGFR2
The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. BMS-817378 is a potent ATP competitive inhibitor of Met/VEGFR2.
In vitro: BMS-794833, which is the active moiety of BMS-817378, is a potent ATP competitive inhibitor of Met/VEGFR2 with IC50 of 1.7 nM/15 nM, also inhibits Ron, Axl and Flt3 with IC50 of <3 nm.="" bms-794833="" also="" inhibits="" met="" receptor="" activated="" gastric="" carcinoma="" cell="" line,="" gtl-16,="" with="" ic50="" of="" 39="" nm="">3>
In vivo: BMS-798433 shows greater than 50% TGI for at least one tumor doubling time with no toxicity observed during 14 days in GTL-16 human gastric tumor xenografts model. BMS-798433 also shows complete tumor stasis at 25 mg/kg against U87 glioblastoma model [1].
Clinical trial: BMS-817378 is now in its ascending multiple-dose study in subjects with advanced cancers.
Reference:[1]http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&adjacent=true&locale=en_EP&FT=D&date=20090730&CC=WO&NR=2009094417A1&KC=A1
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硝酸根从根向地上部茎的长距离运输过程中首先要进行木质部的装载。台湾科学家发现NRT1.5是一个低亲和且依赖于pH的双向转运蛋白,位于质膜并在靠近木质部的中柱鞘细胞中表达,对于硝酸根在木质部的装载具有重要作用。
所以NRT1.5是双向性的转运蛋白
代谢通路:目前在通路数据库(PATHWAY database) 中代谢通路是建立得最好的,有大约90个参考代谢途径的图形。每个参考代谢途径是一个由酶或EC号组成的网络。
QianWang,JessamyTiffen,CharlesG.Bailey,MelanieL.Lehman,WilliamRitchie,LadanFazli,CynthiaMetierre,Yue(Julie)Feng,EstelleLi,MartinGleave,GrantBuchanan,ColleenC.Nelson,JohnE.J.Rasko,JeffHolst
Correspondenceto:JeffHolst,PhD,OriginsofCancerLaboratory,LockedBag6,Newtown,NSW2042Australia.(e-mail:j.holst@centenary.org.au).
BackgroundL-typeaminoacidtransporters(LATs)uptakeneutralaminoacidsincludingL-leucineintocells,stimulatingmammaliantargetofrapamycincomplex1signalingandproteinsynthesis.LAT1andLAT3areoverexpressedatdifferentstagesofprostatecancer,andtheyareresponsIBLeforincreasingnutrientsandstimulatingcellgrowth.
MethodsWeexaminedLAT3proteinexpressioninhumanprostatecancertissuemicroarrays.LATfunctionwasinhibitedusingaleucineanalog(BCH)inandrogen-dependentand-independentenvironments,withgeneexpressionanalyzedbymicroarray.APC-3xenograftmousemodelwasusedtostudytheeffectsofinhibitingLAT1andLAT3expression.ResultswereanalyzedwiththeMann-WhitneyUorFisherexacttests.Allstatisticaltestsweretwo-sided.
ResultsLAT3proteinwasexpressedatallstagesofprostatecancer,withastatisticallysignificantdecreaseinexpressionafter4–7monthsofneoadjuvanthormonetherapy(4–7monthmean=1.571;95%confidenceinterval=1.155to1.987vs0month=2.098;95%confidenceinterval=1.962to2.235;P=.0187).InhibitionofLATfunctionledtoactivatingtranscriptionfactor4–mediatedupregulationofaminoacidtransportersincludingASCT1,ASCT2,and4F2hc,allofwhichwerealsoregulatedviatheandrogenreceptor.LATinhibitionsuppressedM-phasecellcyclegenesregulatedbyE2Ffamilytranscriptionfactorsincludingcriticalcastration-resistantprostatecancerregulatorygenesUBE2C,CDC20,andCDK1.InsilicoanalysisofBCH-downregulatedgenesshowedthat90.9%arestatisticallysignificantlyupregulatedinmetastaticcastration-resistantprostatecancer.Finally,LAT1orLAT3knockdowninxenograftsinhibitedtumorgrowth,cellcycleprogression,andspontaneousmetastasisinvivo.
ConclusionInhibitionofLATtransportersmayprovideanoveltherapeutictargetinmetastaticcastration-resistantprostatecancer,viasuppressionofmammaliantargetofrapamycincomplex1activityandM-phasecellcyclegenes.
L-typeaminoacidtransporters(LATs)supplycellswithlargeneutralaminoacids,whicharenotonlyrequiredforproteinsynthesisbutalsocontributetovarioussignalingpathways.Intracellularleucinelevelsaresensedbytheleucyl-transferRNAsynthetase,previouslyknowntocatalyzetheadenosinetriphosphate–dependentligationofL-leucinetotransferRNAduringproteinsynthesis(1,2).Leucyl-transferRNAsynthetaseactivatestheRagguanosinetriphosphatasecomplexandbindstoRaptortoactivatemammaliantargetofrapamycincomplex1(mTORC1)signalingonthesurfaceoflysosomes(1–3).Inthiswayleucineisnotonlyanessentialaminoacidbutactsasarate-limitingsignalingmoleculeinthemTORC1pathway.
Incellsdeprivedofaminoacids,thereisanaccumulationofunchargedtransferRNA,whichbindstoandactivatesthegeneralcontrolnonrepressed2(GCN2)kinase.Inturn,GCN2phosphorylatesthetranslationinitiationfactor2α(eIF2α)onserine51,triggeringtranslationalupregulationofactivatingtranscriptionfactor(ATF)4(4).ATF4itselfupregulatestheexpressionofaminoacidtransportersasameansofrestoringintracellularaminoacidlevels(5).Therefore,understandinghowaminoacidtransportersregulateintracellularleucinelevels,andgeneratingnovelinhibitorsofthesetransporters,mayleadtopotentsuppressorsofmTORC1signaling.
ThetwodistinctfamiliesofLATsare1)solutecarrier7(SLC7)members(LAT1/SLC7A5andLAT2/SLC7A8),whichmediateNa+-independentneutralaminoacidexchangeasheterodimerswiththe4F2cell-surfaceantigenheavychain(4F2hc/SLC3A2/CD98)glycoprotein(6,7);and2)SLC43proteins(LAT3/SLC43A1andLAT4/SLC43A2)thatmediateNa+-independentuniportofneutralaminoacids(8,9).AlthoughtheexpressionofeachLATmembervariesdramaticallyindifferenttissues,thesetransportersarecommonlyupregulatedincancer.IncreasedLAT1expressionhasbeendetectedinlungcancer,coloncancer,breastcancer,headandneckcancer,genitalcancers,andsofttissuesarcomas(10–12).WeandothershaveshownthatLAT1andLAT3areoverexpressedinprostatecancer(11–14),withLAT1expressionincreasedinmetastasiscomparedwithprimarycancer(10,12).
WehypothesizedthatinhibitionofLAT1andLAT3mayofferaneffectivetherapeuticapproachforprostatecancer.

