MCE E3 连接酶的配体 Ligands for E3 Ligases

www.MedChemE

MedChemExpress

PROTACs

(PROteolysis-TArgetingChimeras)

Handbook

www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

PROTACs(PROteolysis-TArgetingChimeras)

PROTAC,shortforPROteolysis-TArgetingChimera,isaheterobifunctionalnanomoleculecontainingtwodifferentligands;ligandforubiquitinE3andligandfortargetprotein.Thetwopartsareconnectedbyalinkertoforma"three-unit"polymer,targetproteinligand-linker-E3ligaseligand[1].

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

Ub

NH2

E2

E3

Target

Ligase

Protein

PROTAC

Figure1.CompositionofPROTACs[1].

Ub

NH2

Ub

NH2

E2

E2

E3

Target

PROTAC

E3

Target

Ligase

Protein

Ligase

Protein

Ternary

Complex

Catalytic-PROTACisRecycled

Ub

Ub

Ub

Ub

NH2

Target

Protein

PeptideFragments

Proteasome

Polyubiquitination

Figure2.PROTAC-mediateddegradationoftargetproteinsthroughtheUPS[2].

MCE

MasterofBioactiveMolecules

PROTACimprovesthedrugabilityofprotein

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

MechanismofAction

UbiquitinactivatingenzymeE1activatesubiquitinmolecule,thentheactivatedubiquitinmoleculeistransferredtoubiquitinconjugatingenzymeE2.

ThecomplexofubiquitinligaseE3andthetargetproteinbridgedbythePROTACmoleculebindstoE2followingtheinstructionsofE3.

Thetargetproteinislabeledwithubiquitinbecauseoftheincreasedproximityandcollision.

Repeatingthelabelingprocessabove.

Thetargetproteinlabeledwithmultipleubiquitinationsiseventuallyrecognizedanddegradedbytheproteasome.

TableofContents

PROTACs

TargetProteinsforPROTACs

LigandsforTargetProteinsforPROTACsLigandsforE3LigasesPROTACLinkers

BuildingBlocksofConjugates

TargetProteinDegraders

TechnicalRerviceRelatedtoPROTACs

2

3

5

7

9

10

14

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Inhibitors • ScreeningLibraries • Proteins

TargetProteinsforPROTACs

UBI1

Ub

large-subunitribosomalproteinL40A

UBI2

Ub

UBI3

small-subunitribosomalproteinS31

Ub

UBI4

Ub

Ub

Ub

Ub

Ub

Theproteindegradedbytheubiquitin-proteasomepathwayincludecyclin,fusion-associatedprotein,cellsurfacereceptor,transcriptionfactor,tumorsuppressor,oncogeneproduct,abnormalproteinandintracellulardenaturedproteinunderstress.In

shortpeptides

26Sproteasome

ATP

Deubiquitylating

enzymes(DUBs)

Ub

ATP

DUBs

principle,PROTACcanbeusedforthedegradationofalltheaboveproteins.

Atpresent,PROTACmoleculestargetingAR,ER,BTK,IKZF1/3,BRD9,Bcl-xlandIRAK4have

Protein

Protein Ubr1

Rsp5

Ufd4

Tom1

Protein

s~Ub

Ubc1

Ubc2

s~Ub

Rad6

Ubc3

s~Ub

Cdc34

s~Ub

Ubc4

s~Ub

Ubc5

s~Ub

Ubc6

s~Ub

Ubc7

s~Ub

Ubc13

AMP~Ub

Uba1 SH

E1

Uba1

s~Ub

enteredthestageofclinicaldevelopment[3].

BesidesPROTAC,therearealsoothertargetproteindegraders(TPDs)suchasLYTAC,AUTAC,ATTEC,whichcantargetproteinsfromlysosomalpathway[4].

E3 E2

Chaperone-mediatedautophagy(CMA)

LAMP-2A

Substrate translocationcomplex

KFERQ

Figure3.Ubiquitin-proteasomepathway[3]

Microautophagy

Hsc70

Hsc70

Lys-hsc70

Chaperone

complex

LAMP-2A

CYTOSOL

Macroautophagy

LYSOSOME

AMPK

mTOR

Ptdlns3K

ULK

complexcomplex

Nonselective

Autolysosome

At16At5

At16At5

At12

At12

Recycling

LC3-II

p62

LC3-IIp62

Selective

Figure4.

Phagophore

Autophagosome

Lysosomalpathway[4]

1

MCE

MasterofBioactiveMolecules

LigandsforTargetProteinsforPROTACs

AlthoughPROTACtechnologyisdevelopedtosolvethedruggabilityofsomeproteins,PROTACmoleculesnowadaysarebasicallydevelopedbasedonknownproteininhibitors,becausetheligandfortargetproteinshouldbehighlyselectivetoavoidoff-targettoxicityanditcostsmuchtofindsuchanappropriatemolecule.Forexample,theknownstructureofPROTACARV-471isderivedfromTamoxifen,andARV-766isfrom(+)-JQ-1.

O N

N

O

N

HN

N

O

N

O

TamoxifenandARV-471

OH

Cl

Cl

S

S

N

N

N

N

NN

O

NN

O

NH

O

O

O

O

N

S

NH

HON

NOH

O

(+)-JQ-1andARV-110

MCEcanprovideyouwithligandsforthevarioustargetproteinstomeetyourneedsforscientificresearch.Wehavehigh-qualityproductsandservices.Relatedpopularproductsarelistedbelow:

Kinases

EpigeneticFactors

Others

HY-10997

Ibrutinib

Aselective,irreversibleBtkinhibitorcanbeusedasaBTKligandforthesynthesisofP13I.

HY-13001

Quizartinib

Anorallyactive,highlyselectiveandpotentsecond-generationtypeIIFLT3tyrosinekinaseinhibitor.

HY-13030

(+)-JQ-1

Apotent,specific,andreversibleBETbromodomaininhibitorforthefirstandsecondbromodomain(BRD4(1/2)).

HY-129939

PROTACBRD4ligand-1

ApotentBETinhibitor,aligandfortargetBRD4proteinforPROTACTGNE-987.

HY-114872

SLF

AsyntheticligandforFK506-bindingprotein(FKBP)usedinthesynthesisofPROTAC.

HY-A0038

Lasofoxifene(Tartrate)

Anon-steroidalselectiveestrogenreceptormodulator(SERM).

2

www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

Kinases

EpigeneticFactors

Others

HY-44432

Navitoclax-piperazine

AB-celllymphomaextralarge

(BCL-XL)inhibitorusedinthe

synthesisofPROTACDT2216.

HY-126534A

AbemaciclibmetaboliteM18hydrochloride

ACDKinhibitorwithantitumoractivitytodesignPROTACCDK4/6degrader.

HY-130988

Ipatasertib-NH2

AligandfortargetproteinAKTforPROTAC(INY-03-041).

HY-124625

BI-4464

AhighlyselectiveATPcompetitiveinhibitorofPTK2/FAK.

HY-129967

PROTACIRAK4ligand-1

Asyntheticligandforinterleukin-1receptor-associatedkinase4(IRAK4).

HY-130979

EED226-COOH

AnEED226-derivedligandfortargetproteinEEDligandforPROTACUNC6852todegradePRC2.

HY-107445

PROTACBRD9-bindingmoiety1

AcompoundthatbindstoBRD9,andusedforinhibitingBRD9activity,basedonPROTAC.

HY-107443

I-BET762carboxylicacid

AnI-BET762-basedwarheadligandforconjugationreactionsofPROTACtargetingonBET(BRD4).

HY-107451

PROTACBET-bindingmoiety1

Akeyintermediateforthesynthesisofhigh-affinityBETinhibitors.

HY-43723

PROTACBET-bindingmoiety2

AninhibitorofBETbromodomain.

HY-131388

ABM-14

Aligandfortargetingandrogenreceptor(AR)forPROTACARCC-4.

HY-138539

CBP/p300ligand2

AligandfortargetproteinforPROTACofdCBP-1.dCBP-1isapotentandselectivehetero-bifunctionaldegraderofp300/CBP.

HY-131187

BMS-1166-N-piperidine-COOH

ApotentPD-1/PD-L1interactioninhibitorwhichantagonizestheinhibitoryeffectofPD-1/PD-L1immunecheckpointonTcellactivation.

HY-129603

SI-109

ApotentSTAT3SH2domaininhibitor.AligandforSTAT3forPROTAC(SD-36).

HY-133073

CCR7Ligand1

AnallostericligandandantagonistforhumanCCchemokinereceptor

(CCR7).

3

MCE

MasterofBioactiveMolecules

LigandsforE3Ligases

E3ligasesareusuallydividedintodifferentfamiliessuchasRING,HECT,RBR,andeachfamilyincludesmanysub-categories.ThediscoveryofE3ligasesandtheirligandspromotethecontinuousenrichmentofPROTACs.TheligandsofE3ligasesmainlyusednowadaysfocusonthreeligasesnamedcereblon(CRBN),vonHippel-Lindau(VHL)andinhibitorofapoptosisprotein(IAP).CRBNligandsincludethalidomideandotherderivedimmunomodulatoryiminedrugs(IMiDs).VHLligandsincludethelongaminoacidsequenceofHIF-1αproteinanditsderivativeofpeptidomimeticbindingpart.IAPligandsmainlyconsistofpeptidomimeticantagonistsofendogenouscomponents[5].

Inaddition,therearesomeuncommonligandsofE3ligase,includingMDM2,DCAF15,RNF114,DCAF16,KEAP1,andFEM1B.

>>OTHER<<

>>OTHER<<

>>OTHER<<

1%

13%

12%

19%

5%

4%

3%

30%

6%

7%

CRBN

46%

VHL

51%

3%

IAP

9%

32%

7%

10%

8%

8%

26%

Figure5.CommonligandsforE3Ligases[5].

MCEcanprovideLigandsforE3Ligaseswithvariousstructuresandvarieties.Inadditiontocommoncategories,theunusualE3ligandsarealsoincluded.Relatedpopularproductsarelistedbelow:

CRBN

VHL

IAP

HY-10984

Pomalidomide

third-generationimmunomodulatoryagent,actsasmolecularglue.

HY-101763A

(S,R,S)-AHPChydrochloride

AVH032-basedVHLligandusedintherecruitmentofthevonHippel-Lindau(VHL)protein.

HY-128808

cIAP1ligand1

ALCL161derivativebasedIAPligandwhichcanbeconnectedtotheABLligandforproteinbyalinkertoformSNIPER.

4

www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

CRBN

VHL

IAP

HY-23095

Thalidomide-5-OH

AThalidomide-basedcereblonligandusedintherecruitmentofCRBNprotein.

HY-W072954

Lenalidomide-5-Br

ALenalidomide-basedcereblonligandusedintherecruitmentofCRBNprotein.

HY-101291

Iberdomide

Acereblon(CRBN)modulatorusedintherecruitmentofCRBNprotein.

HY-125905

VH032-cyclopropane-F

AVH032-basedVHLligandtoformPROTAC1.

HY-120217

VH032

AVHLligandusedintherecruitmentofthevonHippel-Lindau(VHL)protein.

HY-100947

VH-298

AhighlypotentinhibitoroftheVHLusedinPROTACtechnology.

Others

HY-111856

LCL161-O-Me

ALCL161derivativebasedIAPligandwhichcanbeconnectedtotheABLligandforproteinbyalinkertoformSNIPER.

HY-128806

E3ligaseLigand9

AligandforE3ubiquitinligasetoformPROTACsorSNIPERs.

HY-128810

E3ligaseLigand13

AligandforE3ubiquitinligasetoformPROTACs.

HY-128837

Nutlincarboxylicacid

ANutlin3-basedMDM2ligandcanbeconnectedtotheligandforproteinbyalinkertoformPROTACs.

HY-130842

β-Naphthoflavone-CH2-Br

Anarylhydrocarbonreceptor(AhR)ligandusedtosynthesizeβ-NF-JQ1.

HY-131385

KB02-COOH

AfragmentofsynthesisofubiquitinE3ligaseligandKB02toformKB02-JQ1andKB02-SLF.

HY-130269

β-Naphthoflavone-CH2-OH

Aligandforarylhydrocarbonreceptor(AhR)E3ligase.

HY-13650

Indisulam

AcarbonicanhydraseinhibitorwithanticanceractivityviarecruitmenttoDCAF15.

HY-125292

NV03

ApotentandselectiveantagonistofUHRF1-H3K9me3interactionbybindingtoUHRF1tandemtudordomain.

5

MCE

MasterofBioactiveMolecules

PROTACLinkers

ThelinkerisabridgeconnectingtheE3ligaseligandandtargetproteinligand.Accordingtothecomposition,PROTACLinkerscanbedividedintoPEG,alkylchain,heteroarylchainandotherfragments.Accordingtothefunction,thelinkerscanbedividedintoordinary,clickable,andphoto-switchablelinkers,etc.Accordingtotheconnectingunit,thelinkerscanbeclassifiedintohydroxyl,amino,mercapto,carboxyl,halogen,alkynyl,andazide,etc.

ThereisnomatureschemefortheselectionofPROTAClinkerssolinkersareoptimizedbasedonstructure-activityrelationship.Itisimportanttogetthemodestchainlength,becauselinkerswithtooshortortoolonglengthbothdecreasethedegradationactivity[6].

stericclash

POI

E2

E3

DC50value(nM)

3000

2000

POI

POI

E2

E2

E3

E3

1000

-10 0 10 20

normalizedlinkerlength(#ofatoms)

Figure6.EffectofLinkerlengthonPROTAC’sactivity[6].

MCEcanprovideLigandsforE3ligaseswithvariousstructuresandvarieties.Inadditiontocommoncategories,theunusualE3ligandsarealsoincluded.Relatedpopularproductsarelistedbelow:

AlkylMotifs

HY-30105

HY-107608

HY-133405

N-Boc-piperazine

LeukotrieneB4

Boc-NH-O-C1-NHSester

Amino/aminoconnector.

Carboxyl/hydroxyl/doublebond

Carboxyl/aminoconnector.

connector.

6

www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

AlkylMotifs

HY-W004701

HY-113336B

HY-W014099

Br-C3-methylester

(±)15-HETE

Boc-NH-C4-acid

Halogen/carboxylconnector.

Carboxyl/hydroxyl/doublebond

Carboxyl/aminoconnector.

connector.

HY-40171

HY-W018464

HY-W014831

NH2-C2-NH-Boc

N-Boc-serinol

11-Aminoundecanoicacid

Amino/aminoconnector.

Hydroxyl/aminoconnector.

Amino/carboxylconnector.

PEGMotifs

HY-W008005

HY-W017772

HY-130541

Amino-PEG4-alcohol

Boc-NH-PEG3

Propargyl-PEG2-OH

Amino/hydroxylconnector

Hydroxyl/aminoconnector

Alkyne/hydroxylconnector

HY-W007713

HY-42488

HY-W040246

Fmoc-8-amino-3,6-

Hydroxy-PEG3-(CH2)2-Boc

Fmoc-NH-PEG6-

dioxaoctanoicacid

CH2CH2COOH

Carboxyl/aminoconnector

Hydroxyl/carboxylconnector

Carboxyl/aminoconnector

HY-W004896

HY-22335

HY-W016735

Boc-NH-PEG2

Amino-PEG4-C2-amine

Azido-PEG3-alcohol

Hydroxyl/aminoconnector

Amino/aminoconnector

Azide/hydroxylconnector

ArylandHeterarylMotifs

HY-141263

HY-W008574

HY-113697

Methyltetrazine-acid

TGN-020

Mal-amido-PEG2-C2-amido-

Ph-C2-CO-AZD

Carboxylconnector.

Aminoconnector.

Malconnector.

7

MCE

MasterofBioactiveMolecules

BuildingBlocksofConjugates

MCEcanalsoprovideyouwithTargetProteinLigand-LinkerConjugatesofhottargetproteintomeetyourneedsforscientificresearch.Wehavehigh-qualityproductsandservices.Relatedpopularproductsarelistedbelow:

TargetProteinLigand-LinkerConjugates

HY-44148

FAKligand-LinkerConjugate1

ExtensivelyusedforPROTAC-mediatedproteindegradationofFAK.

HY-141486

DualPARPEGFRligandforPROTAC

UsedinthesynthesisofDP-C-4,whichisCRBN-baseddualPROTACforsimultaneousdegradationofEGFRandPARP.

HY-139403

MRTX849ethoxypropanoicacid

UsedinthesynthesisofPROTACLC-2targetingKRASG12C.

MCEalsoprovidesE3LigaseLigandLinkerConjugateswithnovelanddiversestructuresderivedfromcommonlyusedE3ligandsforrapidconjugationwithrelevanttargetproteinligands.Relatedpopularproductsarelistedbelow:

E3LigaseLigandLinkerConjugates

HY-130737

Pomalidomide4'-alkylC5-acid

AsynthesizedE3ligaseligand-linkerconjugatebasedoncereblonligand.

HY-103608

(S,R,S)-AHPC-(C3-PEG)2-C6-Cl

AsynthesizedE3ligaseligand-linkerconjugatebasedonVHLligand.

HY-103615

Thalidomide-O-amido-C4-N3

AsynthesizedE3ligaseligand-linkerconjugatebasedoncereblonligand.

HY-103600

(S,R,S)-AHPC-PEG1-N3

AsynthesizedE3ligaseligand-linkerconjugatebasedonVHLligand.

HY-122725

Lenalidomide-C5-NH2

AsynthesizedE3ligaseligand-linkerconjugatebasedoncereblonligand.

HY-128812

cIAP1Ligand-LinkerConjugates11

AsynthesizedE3ligaseligand-linkerconjugatebasedonIAPligand.

8

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Inhibitors • ScreeningLibraries • Proteins

TargetProteinDegraders

PROTAC(PROteolysis-TArgetingChimera)isaheterobifunctionalnanomoleculecontainingtwodifferentligands,ligandforubiquitinE3andligandforthetargetprotein.Thetwopartsareconnectedbythelinkertoformatrimercomplex,targetproteinligand-linker-E3ligaseligand.Thepolymerworksbytargetingprotein,usingorganism'sprotein-degradationpathway.

AlongwithPROTAC,therearealsoothertargetproteindegraderssimilartothestructureandmechanismofPROTAClikeLYTAC,AUTACandSNIPER.

Lysosometargetingchimera(LYTAC)degradestargetproteinsviathelysosomalpathwayratherthanthecommonproteasomepathway.LYTACdegradestargetproteinsbybindingtotheasialoglycoproteinreceptoronlysosomethroughitsasialoglycoproteinreceptorligand.AnothersideofLYTACisusuallyanantibodysoitcanbindtothetargetproteinfordegradation[7].

Autophagy-targetingchimera(AUTAC)degradestargetproteinsviathelysosomalpathwayratherthanthecommonproteasomepathway.OneendofAUTACisthetargetproteinligand,theotherendisasiteofK63ubiquitinmodification,andthetwopartsareconnectedbyalinker.AUTACinducesrecognitionofLC3receptorsofautophagosomesbyK63-linkedpolyubiquitinationandthentheTarget-AUTACcomplexisphagocytosedandtransferredintolysosomesfordegradation[8].

SpecificandNon-geneticinhibitorsofapoptosisprotein[IAP]-dependentProteinErasers(SNIPERs),aclassofsmall-moleculedegraders,aredesignedtoinduceIAP-mediatedubiquitylationandproteasomaldegradationoftargetproteins[9].

MCEcanprovideyouwithnovelanddiversePROTACs,LYTACs,AUTACsandSNIPERstomeetyourneedsforscientificresearch.Relatedpopularproductsarelistedbelow:

PROTAC

HY-112588

dBET6

Ahighlypotent,selectiveandcell-permeabledegraderofBETbasedonPROTACwithantitumoractivity.

HY-111556

BSJ-03-123

ApotentandnovelCDK6-selectivesmall-moleculedegrader(PROTAC).

HY-129523

PROTACK-RasDegrader-1

ApotentK-RasdegraderbasedPROTAC,exhibits≥70%degradationefficacyinSW1573cells.

9

MCE

MasterofBioactiveMolecules

PROTAC

HY-16954

ARV-825

ABRD4degraderbasedonPROTACtechnologywhichbindstoBD1andBD2ofBRD4.

HY-139039

BSJ-4-116

AhighlypotentandselectiveCDK12degrader.

HY-129602

SD-36

ApotentandefficaciousPROTACSTAT3degrader.

HY-130615

PROTACEEDdegrader-2

Apolycombrepressivecomplex2(PRC2)inhibitortargetingtheEEDsubunit.

LYTAC

HY-112155

MS4078

Ananaplasticlymphomakinase(ALK)PROTAC.

HY-141438

SIM1

ApotentvonHippel-Lindau(VHL)-basedtrivalentPROTACcapableofdegradationforallBETfamilymembers.

HY-139482

tri-GalNAc-COOH

Anasialoglycoproteinreceptor(ASGPR)ligandthatcanbeusedforLYTACresearch.

HY-145013

tri-GalNAc-COOH(acetylation)

Theacetylatedandmodifiedformoftri-GalNAc-COOH.CanbeusedforthesynthesisofLYTAC.

AUTAC

HY-133869

cGMP-HTL

AmoleculecontainsaHT-ligand,alinkerandtheCys-S-cGMP(autophagytag).

HY-129652

HaloPROTAC1

AligandhavingactivitytobindtoanintracellularproteinsfusedwithHaloTagandastructurehavingactivitytoinduceautophagy.

HY-134640

AUTAC4

AnAUTACwhichcandownregulatecytosolicproteinsandpromotetargetedmitochondrialturnoverviamitophagy.

10

www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

HY-111875

SNIPER(BRD)-1

AdegraderofbothBRD4,cIAP1,cIAP2andXIAP.

HY-122825

SNIPER(ER)-110

Adegradertargetsestrogenreceptor(ER)fordegradationbasedonIAPligand.

HY-111842

PROTACCRABP-IIDegrader-3

Apotentcellularretinoicacidbindingprotein(CRABP-II)degraderbasedonIAPligand.

HY-111871

SNIPER(ABL)-033

APROTACconjugatingHG-7-85-01(ABLinhibitor)toLCL161derivative(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111854

SNIPER(ABL)-015

APROTACconjugatingGNF5(ABLinhibitor)toMV-1(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

SNIPER

HY-111872

SNIPER(ABL)-020

AdegraderofBcr-AblviaDasatinib(ABLinhibitor)andBestatin(IAPligand).

HY-111858

SNIPER(ABL)-050

APROTACconjugatingImatinib(ABLinhibitor)toMV-1(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111851

SNIPER(ABL)-049

APROTACconjugatingImatinib(ABLinhibitor)toBestatin(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111863

SNIPER(ABL)-047

APROTACconjugatingHG-7-85-01(ABLinhibitor)toMV-1(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111874

SNIPER(ABL)-039

APROTACconjugatingDasatinib(ABLinhibitor)toLCL161derivative(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111876

SNIPER(TACC3)-1

AdegradertargetstheTACC3proteinfordegradationbasedonIAPligand.

HY-111861

SNIPER(ABL)-024

APROTACconjugatingGNF5(ABLinhibitor)toLCL161derivative(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

HY-111879

Biotin-BS

APROTACcontainstwodifferentligands,methyl-bestatin(MeBS)forcIAP1andbiotin.

HY-129619

SNIPER(ER)-87

APROTACconjugatedtotheestrogenreceptorα(ERα)ligand4-hydroxytamoxifenbyaPEGlinker,efficientlydegradestheERαprotein.

HY-111859

SNIPER(ABL)-058

APRTACconjugatingImatinib(ABLinhibitor)toLCL161derivative(IAPligand)withalinker,inducesthereductionofBCR-ABLprotein.

11

MCE

MasterofBioactiveMolecules

MolecularGluesasTargetProteinDegraders

Proteindegradationagentsbasedontheubiquitin-proteasomepathwayincludeapartofmolecularglues.Moleculargluesareaclassofsmallmoleculecompoundsthatcaninduceorstabilizetheinteractionbetweenproteins.Ifoneoftheproteinsisubiquitinligase,moleculargluecancauseanotherproteintoundergoubiquitinmodificationanddegradationthroughtheproteasomepathway,whichissimilartoPROTAC[10].

Protein1Protein2

Molecularglue:PROTACwithnolinkerunit

Figure7.Moleculargluemechanism

Autophagosome-tetheringcompound(ATTEC)degradestargetproteinsviathelysosomalpathwayratherthanthecommonproteasomepathway.ATTECdegradestargetproteinsbymoleculargluemechanism,anditsmolecularweightissmallerthanAUTAC.ATTECsshortenthedistancebetweenLC3receptorandtargetproteinandthenthetargetproteinisphagocytosedandtransferredintolysosomefordegradation[11].

HTS

ATTEC

F

Cl

Br

HN

N

HN

O

O

NN

O

O

OH

Br

Br

Br

O

HN

HO

OH

HO

OO

10O5

8F20

AN1

AN2

Figure8.StructureofATTECs[11].

MCEcanprovideyouwithmoleculargluesandATTECstomeetyourneedsforscientificresearch.Relatedpopularproductsarelistedbelow:

MolecularGlues

ATTEC

HY-129395

Mezigdomide

AcereblonE3ubiquitinligasemodulatingdrug,actsasamolecularglue.

HY-130800

Eragidomide

Afirst-in-classGSPT1-selectivecereblonE3ligasemodulator,actsasamolecularglue.

HY-130258

LC3-mHTT-IN-AN1

AmHTT-LC3linkercompound,whichinteractswithbothmutanthuntingtinprotein(mHTT)andLC3BbutnotwithwtHTTorirrelevantcontrolproteins.

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www.MedChemE

Inhibitors • ScreeningLibraries • Proteins

TechnicalServiceRelatedtoPROTACs

MCEcanprovideone-stopservicesforthedesign,synthesis,analysis,purification,optimization,detectionandevaluationofPROTAC-relatedproducts(LigandsforE3Ligases,PROTACLinkers,LigandsforTargetProteinforPROTACs,E3LigaseLigand-LinkerConjugates,TargetProteinLigand-LinkerConjugates,PROTACs,SNIPERs,PROTAC-LinkerConjugatesforPAC).Forthetargetproteinswithunknownligands,wehaveavarietyofcompoundlibrariesandvirtualscreeninglibrariesasthebasistoscreenprotein-relatedligandsandconstructappropriatePROTACmolecules.

SynthesisserviceofLigandsfor

Synthesisserviceof

SynthesisserviceofLigandsfor

TargetProteinsforPROTACs

PROTACLinkers

E3Ligases

Screening,synthesisandmodificationof

Synthesisandmodification

Synthesisandmodificationof

LigandsforTargetProteins

ofLinkers

LigandsforE3Ligases

TargetProtein

+

PROTAC

+

E3Ligase

Ligand

Linker

Ligand

Synthesisserviceof

TargetProteinLigand-Linker

TargetProtein

Conjugates

LigandLinkerConjugate

Synthesisandmodificationof

TargetProteinLigand-Linker

Conjugates

Synthesisserviceof

E3Ligase

E3LigaseLigand-Linker

Conjugates

LigandLinkerConjugate

Synthesisandmodificationof

E3LigaseLigand-Linker

Conjugates

PROTAC,SNIPER,

Customizationandphysicochemical

propertiesdeterminationof

PROTAC-LinkerConjugateforPAC,…

PROTACrelatedmolecules

SynthesisserviceofPROTACs

SynthesisserviceofSNIPERs

Synthesisserviceof

PROTAC-LinkerConjugatesforPACs

Design,synthesisandmodification

Design,synthesisandmodificationofPROTACs

Design,synthesisandmodificationof

ofSNIPERs

PROTAC-LinkerConjugatesforPACs

OnlineConsulting:

ThecorrespondingschemeandpriceforPROTACshallbedeterminedafterevaluation.Forfurtherinformationonservicepricingortechnicaldetails,pleaseemailsales@MedChemEorcontactMCEsalesstaffdirectly.

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MCE

MasterofBioactiveMolecules

ElementsofPROTACs

PROTACmoleculesaregenerallycomposedofthreeparts:LigandforTargetProtein,LinkerandLigandforE3Ligase.

1.SelectionofLigandforE3Ligase

E3ligaseisakeystructurefortargetproteinubiquitination.Itsligandsincludemanytypes,amongwhichCRBN(Cereblon),VHL(vonHippel-Lindau),IAPandMDM2arenowfrequentlyused.LigandsofCRBNwithgooddrug-likenessaregeneral