MedKoo Biosciences/GSK1070916/205477/25mg

Synonym:GSK1070916;GSK-1070916;GSK1070916;GSK1070916A;GSK-1070916A;GSK1070916A;NMI-900;NMI900;NMI900.

IUPAC/ChemicalName:3-(4-(4-(2-(3-((dimethylamino)methyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl)phenyl)-1,1-dimethylurea.

InChiKey:QTBWCSQGBMPECM-UHFFFAOYSA-N

InChiCode:InChI=1S/C30H33N7O/c1-6-37-19-26(28(34-37)21-10-12-23(13-11-21)32-30(38)36(4)5)24-14-15-31-29-25(24)17-27(33-29)22-9-7-8-20(16-22)18-35(2)3/h7-17,19H,6,18H2,1-5H3,(H,31,33)(H,32,38)

SMILESCode:O=C(NC1=CC=C(C2=NN(CC)C=C2C3=C4C(NC(C5=CC=CC(CN(C)C)=C5)=C4)=NC=C3)C=C1)N(C)C

TechnicalData

AdditionalInformation

 GSK1070916isanovelATPcompetitiveinhibitorthatishighlypotentandselectiveforAuroraB/Ckinases.HumantumorcellstreatedwithGSK1070916showdose-dependentinhibitionofphosphorylationonserine10ofHistoneH3,asubstratespecificforAuroraBkinase.Moreover,GSK1070916inhibitstheproliferationoftumorcellswithEC(50)valuesof<10nmol/Linover100celllinesspanningabroadrangeoftumortypes.AlthoughGSK1070916haspotentactivityagainstproliferatingcells,adramaticshiftinpotencyisobservedinprimary,nondividing,normalhumanveinendothelialcells,consistentwiththeproposedmechanism.Wefurtherdeterminedthattreatedcellsdonotarrestinmitosisbutinsteadfailtodivideandbecomepolyploid,ultimatelyleADIngtoapoptosis.GSK1070916showsdose-dependentinhibitionofphosphorylationofanAuroraB-specificsubstrateinmiceandconsistentwithitsbroadcellularactivity,hasantitumoreffectsin10humantumorxenograftmodelsincludingbreast,colon,lung,andtwoleukemiamodels.TheseresultsshowthatGSK1070916isapotentAuroraB/Ckinaseinhibitorthathasthepotentialforantitumoractivityinawiderangeofhumancancers.[MolCancerTher2009;8(7):1808–17] 
 
 
 

References

1:MoyC,OleykowskiCA,PlantR,GreshockJ,JingJ,BachmanK,HardwickeMA,WoosterR,DegenhardtY.HighchromosomenumberinhematologicalcancercelllinesisanegativepredictorofresponsetotheinhibitionofAuroraBandCbyGSK1070916.JTranslMed.2011Jul15;9:110.doi:10.1186/1479-5876-9-110.PubMedPMID:21762492;PubMedCentralPMCID:PMC3146841.

2:ZhangB,LiY,ZhangH,AiC.3D-QSARandMolecularDockingStudiesonDerivativesofMK-0457,GSK1070916andSNS-314asInhibitorsagainstAuroraBKinase.IntJMolSci.2010Nov2;11(11):4326-47.doi:10.3390/ijms11114326.PubMedPMID:21151441;PubMedCentralPMCID:PMC3000085.

3:AdamsND,AdamsJL,BurgessJL,ChaudhariAM,CopelandRA,DonatelliCA,DrewryDH,FisherKE,HamajimaT,HardwickeMA,HuffmanWF,Koretke-BrownKK,LaiZV,McDonaldOB,NakamuraH,NewlanderKA,OleykowskiCA,ParrishCA,PatrickDR,PlantR,SarpongMA,SasakiK,SchmidtSJ,SilvaDJ,SuttonD,TangJ,ThompsonCS,TumminoPJ,WangJC,XiangH,YangJ,DhanakD.DiscoveryofGSK1070916,apotentandselectiveinhibitorofAuroraB/Ckinase.JMedChem.2010May27;53(10):3973-4001.doi:10.1021/jm901870q.PubMedPMID:20420387.

4:MedinaJR,GrantSW,AxtenJM,MillerWH,DonatelliCA,HardwickeMA,OleykowskiCA,LiaoQ,PlantR,XiangH.DiscoveryofanewseriesofAurorainhibitorsthroughtruncationofGSK1070916.BioorgMedChemLett.2010Apr15;20(8):2552-5.doi:10.1016/j.bmcl.2010.02.091.Epub2010Mar1.PubMedPMID:20335034.

5:HardwickeMA,OleykowskiCA,PlantR,WangJ,LiaoQ,MossK,NewlanderK,AdamsJL,DhanakD,YangJ,LaiZ,SuttonD,PatrickD.GSK1070916,apotentAuroraB/Ckinaseinhibitorwithbroadantitumoractivityintissueculturecellsandhumantumorxenograftmodels.MolCancerTher.2009Jul;8(7):1808-17.doi:10.1158/1535-7163.MCT-09-0041.Epub2009Jun30.PubMedPMID:19567821.

6:AndersonK,LaiZ,McDonaldOB,StuartJD,NarteyEN,HardwickeMA,NewlanderK,DhanakD,AdamsJ,PatrickD,CopelandRA,TumminoPJ,YangJ.BiochemicalcharacterizationofGSK1070916,apotentandselectiveinhibitorofAuroraBandAuroraCkinaseswithanextremelylongresidencetime1.BiochemJ.2009May13;420(2):259-65.doi:10.1042/BJ20090121.PubMedPMID:19284385.