Synonym:E7050;E-7050;E7050;Golvatinib.

IUPAC/ChemicalName:N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

InChiKey:BWEYRDZIIMFBJR-UHFFFAOYSA-N

InChiCode:InChI=1S/C33H37F2N7O4/c1-39-16-18-40(19-17-39)23-9-14-41(15-10-23)32(45)38-29-21-26(8-13-37-29)46-25-6-7-28(27(35)20-25)42(24-4-2-22(34)3-5-24)31(44)33(11-12-33)30(36)43/h2-8,13,20-21,23H,9-12,14-19H2,1H3,(H2,36,43)(H,37,38,45)

SMILESCode:O=C(C1(C(N)=O)CC1)N(C2=CC=C(OC3=CC(NC(N4CCC(N5CCN(C)CC5)CC4)=O)=NC=C3)C=C2F)C6=CC=C(F)C=C6

TechnicalData

AdditionalInformation

E7050isthefirstkinaseinhibitorwithdualactionagainstbothc-MetandVEGFR-2.ThedualinhibitoryactivityofE7050againsttumorgrowthandangiogenesisresultsindrastictumorregressionanddisappearanceandalsoprolongationofLifespanwithoutadverseeffects. E7050iscurrentlyunderevaluationinaphaseIclinicaltrial.   (CancerSci.2010Jan;101(1):210-5.Epub2009Sep2.).
E7050isthefirstkinaseinhibitorwithdualactionagainstbothc-MetandVEGFR-2.ThedualinhibitoryactivityofE7050againsttumorgrowthandangiogenesisresultsindrastictumorregressionanddisappearanceandalsoprolongationoflifespanwithoutadverseeffects. E7050iscurrentlyunderevaluationinaphaseIclinicaltrial.   (
).
   
  
E7050circumventedresistancetoallofthereversIBLe,irreversible,andmutant-selectiveEGFR-TKIsinducedbyexogenousand/orendogenousHGFinEGFRmutantlungcancercelllines,byblockingtheMet/Gab1/PI3K/Aktpathwayinvitro.E7050alsopreventedtheemergenceofgefitinib-resistantHCC827cellsinducedbycontinuousexposuretoHGF.Intheinvivomodel,E7050plusgefitinibresultedinmarkedregressionoftumorgrowthassociatedwithinhibitionofAktphosphorylationincancercells.CONCLUSIONS:AnewMetkinaseinhibitor,E7050,reversesthethreeHGF-inducedmechanismsofgefitinibresistance,suggestingthatE7050mayovercomeHGF-inducedresistancetogefitinibandnext-generationEGFR-TKIs.(source:ClinCancerRes.2012Mar15;18(6):1663-71.Epub2012Feb8.)
E7050circumventedresistancetoallofthereversible,irreversible,andmutant-selectiveEGFR-TKIsinducedbyexogenousand/orendogenousHGFinEGFRmutantlungcancercelllines,byblockingtheMet/Gab1/PI3K/Aktpathwayinvitro.E7050alsopreventedtheemergenceofgefitinib-resistantHCC827cellsinducedbycontinuousexposuretoHGF.Intheinvivomodel,E7050plusgefitinibresultedinmarkedregressionoftumorgrowthassociatedwithinhibitionofAktphosphorylationincancercells.CONCLUSIONS:AnewMetkinaseinhibitor,E7050,reversesthethreeHGF-inducedmechanismsofgefitinibresistance,suggestingthatE7050mayovercomeHGF-inducedresistancetogefitinibandnext-generationEGFR-TKIs.(source:
)

References

1:NakagawaT,TakeuchiS,YamadaT,NanjoS,IshikawaD,SanoT,KitaK,NakamuraT,MatsumotoK,SudaK,MitsudomiT,SekidoY,UenakaT,YanoS.CombinedTherapywithMutant-SelectiveEGFRInhibitorandMetKinaseInhibitorforOvercomingErlotinibResistanceinEGFR-MutantLungCancer.MolCancerTher.2012Oct;11(10):2149-57.doi:10.1158/1535-7163.MCT-12-0195.Epub2012Jul25.PubMedPMID:22844075.

2:TakeuchiS,WangW,LiQ,YamadaT,KitaK,DonevIS,NakamuraT,MatsumotoK,ShimizuE,NishiokaY,SoneS,NakagawaT,UenakaT,YanoS.DualinhibitionofMetkinaseandangiogenesistoovercomeHGF-inducedEGFR-TKIresistanceinEGFRmutantlungcancer.AmJPathol.2012Sep;181(3):1034-43.doi:10.1016/j.ajpath.2012.05.023.Epub2012Jul9.PubMedPMID:22789825.

3:WangW,LiQ,TakeuchiS,YamadaT,KoizumiH,NakamuraT,MatsumotoK,MukaidaN,NishiokaY,SoneS,NakagawaT,UenakaT,YanoS.MetkinaseinhibitorE7050reversesthreedifferentmechanismsofhepatocytegrowthfactor-inducedtyrosinekinaseinhibitorresistanceinEGFRmutantlungcancer.ClinCancerRes.2012Mar15;18(6):1663-71.Epub2012Feb8.PubMedPMID:22317763.

4:GreenDR.'Tit-for-tat'incellBIOLOGy.NatRevMolCellBiol.2011Feb;12(2):73.PubMedPMID:21252991.

5:NakagawaT,TohyamaO,YamaguchiA,MatsushimaT,TakahashiK,FunasakaS,ShirotoriS,AsadaM,ObaishiH.E7050:adualc-MetandVEGFR-2tyrosinekinaseinhibitorpromotestumorregressionandprolongssurvivalinmousexenograftmodels.CancerSci.2010Jan;101(1):210-5.Epub2009Sep2.PubMedPMID:19832844.