MCE E3 连接酶的配体 Ligands for E3 Ligases.docx

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MCE E3 连接酶的配体 Ligands for E3 Ligases.docx

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www.MedChemE

MedChemExpress

PROTACs

(PROteolysis-TArgetingChimeras)

Handbook

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

PROTACs(PROteolysis-TArgetingChimeras)

PROTAC,shortforPROteolysis-TArgetingChimera,isaheterobifunctionalnanomoleculecontainingtwodifferentligands;ligandforubiquitinE3andligandfortargetprotein.Thetwopartsareconnectedbyalinkertoformathree-unitpolymer,targetproteinligand-linker-E3ligaseligand[1].

OncethePROTACmoleculeentersthecell,ligandforproteinofinterest(POI)canspecificallybindtothecorrespondingtargetprotein,whileE3ligaseligandcanrecruitE3ligasetoformthetrimercomplexofPOI-Linker-E3ligase,inwhichE3ligasemediatesubiquitinationonPOIbyubiquitinfromenzymeE2.POIlabeledbyubiquitinisrecognizedanddegradedbytheproteasomesystem.ItisnotnecessaryforPOIligandtooccupythebindingsiteforalongtimeduringthisprogressbecauseofinstantaneousubiquitinationafterthetransientformationoftheternarycomplex,soPROTACcanbereusedmanytimesincells[2].

NH2

Target

Ligase

Protein

PROTAC

Figure1.CompositionofPROTACs[1].

NH2

Target

PROTAC

Target

Ligase

Protein

Ligase

Protein

Ternary

Complex

Catalytic-PROTACisRecycled

NH2

Target

Protein

PeptideFragments

Proteasome

Polyubiquitination

Figure2.PROTAC-mediateddegradationoftargetproteinsthroughtheUPS[2].

MCE

MasterofBioactiveMolecules

PROTACimprovesthedrugabilityofprotein

Comparedwithtraditionalsmallmoleculeswhichneedtoknowthebindingsiteandmechanismoftargetprotein,PROTACignoresthemechanismofthetargetproteinitselfanddirectlydegradestargetproteinafterubiquitinlabeling.Inaddition,duetoitsspecificmechanism,itrequiresonlyasmallamounttobeeffective,oftenatthenanomolarlevel.PROTACisdevoidofdrugresistance,andhasbecomeasolutiontotheundruggableproblemofmanytumorin