Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2 英文参考文献.docVIP

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Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2 英文参考文献.doc

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Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2 英文参考文献

DifferentialInhibitorSensitivitybetweenHumanKinases VRK1andVRK2 MartaVa′zquez-Cedeira1,IriaBarcia-Sanjurjo2,MartaSanz-Garc?′a1,RamiroBarcia2,PedroA.Lazo1* 1ExperimentalTherapeuticsandTranslationalOncologyProgram,InstitutodeBiolog?′aMolecularyCelulardelCa′ncer,CSIC-UniversidaddeSalamanca,Salamanca,Spain, 2DepartamentodeBioqu?′micayBiolog?′aMolecular,FacultaddeVeterinaria,UniversidaddeSantiagodeCompostela,Lugo,Spain Abstract Humanvaccinia-relatedkinases(VRK1andVRK2)areatypicalactiveSer-Thrkinasesimplicatedincontrolofcellcycleentry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differencesinVRKcatalyticsitesmakethemsuitablecandidatesfordevelopmentofspecificinhibitors.Inthisworkwehave determinedthesensitivityofVRK1andVRK2tokinaseinhibitors,currentlyusedinbiologicalassaysorinpreclinicalstudies, inordertodiscriminatebetweenthetwoproteinsaswellaswithrespecttothevacciniavirusB1Rkinase.BothVRKproteins andvacciniaB1RarepoorlyinhibitedbyinhibitorsofdifferenttypestargetingSrc,MEK1,B-Raf,JNK,p38,CK1,ATM,CHK1/2 andDNA-PK,andmostofthemhavenoeffectevenat100mM.Despitetheirlowsensitivity,someoftheseinhibitorsinthe lowmicromolarrangeareabletodiscriminatebetweenVRK1,VRK2andB1R.VRK1ismoresensitivetostaurosporine,RO- 31-8220andTDZD8.VRK2ismoresensitivetoroscovitine,RO31–8220,Cdk1inhibitor,AZD7762,andIC261.Vacciniavirus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a differentpatternofsensitivitytokinaseinhibitors.Thisdifferentialresponsetoknowninhibitorscanprovideastructural frameworkforVRK1orVRK2specificinhibitorswithlowornocross-inhibition.ThedevelopmentofhighlyspecificVRK1 inhibitorsmightbeofpotentialclinicaluseinthosecancerswherethesekinasesidentifyaclinicalsubtypewithapoorer prognosis,asisthecaseofVRK1inbreastcancer. Citation: Va′zquez-Cedeira M, Barcia-Sanjurjo I, Sanz-Garc?′a M, Barcia R, Lazo PA (2011) Differential Inhibitor Sensitivity betw