细胞周期靶向的药物筛选

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1、Cell-cycle-targetingDrugsSunHongPharm-ToxTeamIntroductionManyexistingcancerchemotherapiesinterferewithDNAreplicationandformationofthemitoticspindle,thatis,theprocessescentraltothecellcycle.Alternativestrategiesaimedattargetingcell-cyclecomponentsthatarespecificallyderegul

2、atedintumourcellsarenowbeingexplored.Severalgroupsofproteinkinasesassociatedwithaberranttumourcell-cyclecheckpointsareusedastargetsforthediscoveryofsmall-moleculeinhibitor.Thefirstofthesecompoundsarenowbeingevaluatedintheclinic.Conventionalcell-cycle-relatedstrategiesinon

3、cologyDNA-damagingagentsAntimetabolitesTopoisomeraseinhibitorsAgentsthatdisruptthemicrotubulesofthemitoticspindleNewcell-cycle-relatedstrategiesinoncologyNormalcellsrelyonmitogenicstimulationtoenterthecycle.Cancercellsenterandstayincyclepermanently,leadingtotheuncheckedgr

4、owthoftumours.Furthermore,DNAandspindlecheckpointsarealsofrequentlyoverriddenintransformedcells.Reinstatingcell-cyclecontrolviapharmacologicaltargetingofderegulatedcomponentsofthecheckpointpathwaysshouldbeaviablestrategyinanticancertherapy.ThemammaliancellcycleCell-cycle-

5、targetingDrugsDrugstargetingG1/SG2checkpointabrogatorsMitosisanditsdrugtargetsTargetingG1/SThemainstayofcell-cycle-targetedtherapeuticstrategies,untilrecently,hasbeenpharmacologicalreinstatementofG1/Schecksintumourcells.EarlyapproacheswerebasedongenetherapywithCDK-directe

6、dtumour-suppressorproteins.Morerecently,theseindirectapproacheshavebeensupplantedbysmall-moleculeagents,especiallyCDKinhibitors.G2checkpointabrogatorsThemainpurposeoftheG2checkpointistoallowtimeforthecelltorepairdamagedDNAbeforemitoticentry.AsaconsequenceofG1checkpointdef

7、ects,tumourcellsappeartodependontheG2checkpointmorethannormallyproliferatingcells.Abrogationofthischeckpointshould,therefore,denytumourcellstheopportunitytorepairdamagedDNAandshouldsensitisethemtowardsDNAdamagingchemotherapy.KinaseinhibitorswithG2-checkpointabrogatingprop

8、ertiesMethylxanthinederivativescaffeinePentoxyfillineIndolocarbazolessuchasUCN-01andSB-218078Mit