细胞周期靶向的药物筛选.ppt

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

2、intumourcellsarenowbeingexplored.Severalgroupsofproteinkinasesassociatedwithaberranttumourcell-cyclecheckpointsareusedastargetsforthediscoveryofsmall-moleculeinhibitor.Thefirstofthesecompoundsarenowbeingevaluatedintheclinic.Conventionalcell-cycle-relatedstrategiesinoncologyDN

3、A-damagingagentsAntimetabolitesTopoisomeraseinhibitorsAgentsthatdisruptthemicrotubulesofthemitoticspindleNewcell-cycle-relatedstrategiesinoncologyNormalcellsrelyonmitogenicstimulationtoenterthecycle.Cancercellsenterandstayincyclepermanently,leadingtotheuncheckedgrowthoftumour

4、s.Furthermore,DNAandspindlecheckpointsarealsofrequentlyoverriddenintransformedcells.Reinstatingcell-cyclecontrolviapharmacologicaltargetingofderegulatedcomponentsofthecheckpointpathwaysshouldbeaviablestrategyinanticancertherapy.ThemammaliancellcycleCell-cycle-targetingDrugsDr

5、ugstargetingG1/SG2checkpointabrogatorsMitosisanditsdrugtargetsTargetingG1/SThemainstayofcell-cycle-targetedtherapeuticstrategies,untilrecently,hasbeenpharmacologicalreinstatementofG1/Schecksintumourcells.EarlyapproacheswerebasedongenetherapywithCDK-directedtumour-suppressorpr

6、oteins.Morerecently,theseindirectapproacheshavebeensupplantedbysmall-moleculeagents,especiallyCDKinhibitors.G2checkpointabrogatorsThemainpurposeoftheG2checkpointistoallowtimeforthecelltorepairdamagedDNAbeforemitoticentry.AsaconsequenceofG1checkpointdefects,tumourcellsappearto

7、dependontheG2checkpointmorethannormallyproliferatingcells.Abrogationofthischeckpointshould,therefore,denytumourcellstheopportunitytorepairdamagedDNAandshouldsensitisethemtowardsDNAdamagingchemotherapy.KinaseinhibitorswithG2-checkpointabrogatingpropertiesMethylxanthinederivati

8、vescaffeinePentoxyfillineIndolocarbazolessuchasUCN-01andSB-218078Mit