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1、Bioorganic&MedicinalChemistry21(2013)4020–4026ContentslistsavailableatSciVerseScienceDirectBioorganic&MedicinalChemistryjournalhomepage:www.elsevier.com/locate/bmcDirecttargetingofb-catenin:Inhibitionofprotein–proteininteractionsfortheinactivationofWntsignalingGernotHahne,TomN
2、.Grossmann⇑ChemicalGenomicsCentreoftheMaxPlanckSociety,Otto-Hahn-Str.15,44227Dortmund,GermanyarticleinfoabstractArticlehistory:TheactivationofdevelopmentalsignalingpathwayssuchasNotch,HedgehogandWnthasimplicationsAvailableonline22March2013intheonsetandprogressionofnumeroustype
3、sofcancer.Consequently,targetingofsuchpathwaysisconsideredanattractivetherapeuticapproach.InhibitionoftheWntsignalingcascadeprovestobecom-Keywords:plicated,inpart,duetothelackofdruggablepathwaycomponents.ThecentralhubinWntsignalingisb-Catenintheproteinb-catenin,whichisinvolved
4、innumerousprotein–proteininteractions.Ingeneral,theWntsignalinginhibitionofprotein–proteininteractionsischallenginginparticularwithbindinginterfaceslackingProtein–proteininteractionpronouncedhydrophobicpockets.Herein,wegiveanoverviewofb-catenin–proteininteractions,andCancerwer
5、eviewactiveagentsthatwerereportedtoinhibitcanonicalWntsignalingviadirecttargetingofTranscriptionfactorb-catenin.Ó2013ElsevierLtd.Allrightsreserved.1.Introductionintoamulti-proteincomplexcomprisingtheproteinsAxin,ade-nomatouspolyposiscoli(APC),andthetwoserine-threonineki-Thedev
6、elopmentoftumorsisamultistepprocessandinvolvesnases,glycogensynthasekinase3b(GSK3b)aswellascaseintheevolutionofwild-typeintocancercells.Thistransformationiskinase1a(CK1a),amongothers(Scheme1).Thissocalleddestruc-accompaniedbytheacquisitionofcertainhallmarksincludingtioncomplex
7、triggersphosphorylationofspecificsitesintheN-ter-sustainedproliferation,activatedinvasionandreplicativeimmor-minalregionofb-cateninleadingtoubiquitinationbyanE31tality.Mostoftenanimplementationofthesehallmarksisfacili-ubiquitinligasecomplex,andfinallytoproteasomaldegradation5tat
8、edbyhyperactivationofparticularsignalingpathways.Amongofb-cat
