2009 Nature Review Drug Discov. Cell cycle kinase

Withinthehumangenome,~300geneshavebeenfoundtobemutatedincancer(CatalogueofSomaticMutationsinCancerattheWellcomeTrustSangerInstitute;seeFurtherinformation),andmanymoreexhibitalteredlevelsorpatternsofexpression.Suchchangescontrib-utetoderegulationofcellcyclekinases,whichisoftenassociatedwithaberrantdivisionanduncontrolledproliferationofcancercells.Sincetheelucidationofthemechanismsofmammaliancelldivisioninthe1970sand1980sbytheworkofLeeHartwell,PaulNurseandTimHunt1,geneproductsthatregulatethekeycellcyclemachineryhavebeeninvestigatedascancerdrugtargets.Theseincludethecyclin-dependentkinases(CDKs),whichhavebeenestablishedasmasterregulatorsofcellproliferation,andmorerecentlyidentifiedpotentialtargets,suchasproteinkinasesthatcoordinatethecell-ularresponsetoDNAdamageandproteinkinasesthatregulatemitosis(FIG.1).Thesearchforsyntheticinhibitorsofproteinkinasesasanticancerdrugshasbeeninvigoratedbythesuccessfulapprovalofanumberofmoleculesthattargettyrosinekinases,suchastheBCR–ABLproteinkinaseinhibitorimatinib(Gleevec;Novartis)forthetreatmentofchronicmyelogenousleukaemia.Moreover,agrowingbodyofstructuralinformationaboutthecellcycleproteinkinases,mainlyCDKsincomplexwiththeirregula-torysubunitsandsyntheticinhibitors,hasfacilitatedthedevelopmentofpotentialtherapeuticcompounds.However,theexploitationofcellcycleproteinkinaseinhibitorsinclinicaloncologyhasnotyetachievedproofofconcept,asnosuchmoleculehasbeenapprovedasananticancerdrug.Futureapproachesshouldthereforecombinethelessonslearnedfromtheearlyworkusingsmall-moleculeinhibitorswiththerecentincreasedunderstandingofthederegulationofcellcycleproteinkinasesincancer.ProteinkinasesinthemammaliancellcycleDuringthemammaliancellcycle,progressionthroughthefirstgap(G1)phaseandinitiationoftheDNAsyn-thesis(S)phaseiscooperativelyregulatedbyseveralcyclinsandtheirassociatedCDKs,whichintegratetheflowofinformationfromoutsidethecell,includinggrowthfactorsignallingandtheavailabilityofnutrients.Whencellsinthequiescent(G0)phaseenterthecycle,CDK4andCDK6formactivecomplexeswithD-typecyclins(D1,D2andD3)andinitiatephosphorylationoftheretino-blastomaprotein(RB1;alsoknownasp105-RB)andpossiblyothermembersofthe‘pocket’proteinfamily2,3(BOX1),whichinactivatestheirfunctionastranscriptionalrepressors.InlateG1,activeCDK2–cyclinEheterodi-mersreinforceRB1phosphorylationonadditionalsites,inafeedforwardactiontoirreversiblyinitiatethegeneexpressionprogrammeoftheSphase.Thisstage,calledtherestrictionpoint,iscrucialincancerasalterationsinthekeyregulatoryplayersintheG1toSphasetran-sitioncouldallowcellstoproliferateindependentlyofmitogenicstimuli(BOX2).Beyondtherestrictionpoint,RB1ismaintainedinahyperphosphorylatedstatebythesequentialactivitiesofcyclinA–CDK2,cyclinA–CDK1andcyclinB–CDK1complexes,therebyensuringcellcycleprogression.However,inthecaseofDNAdamage,the*OncologyResearchCentreofMercogliano,Mercogliano,Avellino,Italy.‡DepartmentofHumanPathologyandOncology,UniversityofSiena,Siena,Italy.§SbarroInstituteforCancerResearchandMolecularMedicine,CenterforBiotechnology,TempleUniversity,Philadelphia,USA.CorrespondencetoS.L.andA.G.e‑mails:[e-mail];[e-mail]:10.1038/nrd2907CyclinsAfamilyofproteinsthatareinvolvedincellcycleprogression.Theyaretransientlyexpressedinresponsetogrowthsignalsinordertoregulatethetimelyactivationofcyclin-dependentkinases.CellcyclekinasesastherapeutictargetsforcancerSilviaLapenna*‡andAntonioGiordano‡§Abstract|Severalfamiliesofproteinkinasesorchestratethecomplexeventsthatdrivethecellcycle,andtheiractivityisfrequentlyderegulatedinhyperproliferativecancercells.Althoughseveralmoleculesthatinhibitcellcyclekinaseshavebeendevelopedandclinicallyscreenedaspotentialanticanceragents,noneofthesehasbeenapprovedforcommercialuseandaneffectivestrategytospecificallycontrolmalignantcellproliferationhasyettobeestablished.However,recentgeneticandbiochemicalstudieshaveprovidedinformationabouttherequirementforcertaincellcyclekinasesbyspecifictumoursandspecializedtissuetypes.Here,wediscussthepotentialandlimitationsofestablishedcellcyclekinasesastargetsinanticancerdrugdiscoveryaswellasnovelstrategiesforthedesignofnewagents.REVIEWSNATuREREvIEWS|DrugDiscoveryvoLuME8|juLy2009|547©2009MacmillanPublishersLimited.AllrightsreservedNatureReviews|DrugDiscoverySpindleassemblySpindleassemblycheckpointDNAdamagecheckpointRestrictionpointChromosomecondensationCentrosomeduplicationDNAreplicationRBinactivationCytokinesisMSG2G1G0MitogenicsignalsMelanoma,glioblastomaandosteosarcoma,andbreastandcervicalcancersLymphomas,squamouscellcancerandgliomaBladder,colon,ovaryandothercancersColorectal,lungandpancreatictumoursandTcelllymphomasColorectalcancer,lymphomas,MVAandPCSSLymphomasandbreastcancerStomach,endometrialandbreastcancerStomach,endometrial,colorectalandlungcancersCancersoftheliver,lung,stomachandepidermis.Severalhumantumours,forexample,breastandcolorectalcancersCDK4CDK6AuroraBBUB1BUB1BBUB3MPS1ATMATRCHK1CDK1PLK1AuroraACDK2CHK2CellcyclecheckpointsAseriesofsurveillancepathwayswhichensurethatcellspassaccuratecopiesoftheir