MCE 癌癥免疫治療 Cancer Immunotherapy

www.MedChemE

MedChemExpress

CancerResearch

ProductHandbook

Escaping

tumourcell

CD4+

Tcell

Neutrophil

iNOS

ROS

NKcell

Tumourcell

TGFβ

ATP

Adenosine

IL-2

TGFβ,

IL-10

Bregcell

IL-12

CTL

(N-)CCL2

CCL2

Monocyte

iNOS

CCL17,

CCL22

TAM

Tregcell

MHC

IL-10

CCL5,

classII

CXCL5

Lipid

droplets

DC

Reference:

HannahGarner,KarinEdeVisser.Immunecrosstalkin

cancerprogressionandmetastaticspread:acomplexconversation.

NatRevImmunol.2020Aug;20(8):483-497.

DEATHS

1lN6

MCE

MasterofBioactiveMolecules

Cancer

Introduction

Withtheincreaseofmorbidityandmortalityworldwide,cancerhasbecometheleadingcauseofdeathandaglobal

publichealthproblem.AccordingtostatisticsoftheWHOReportonCancer2020,therewereanestimated18.1millionnewcasesand9.6milliondeathsfromcancer.

In2018,lungcancerwasthemostfrequentlydiagnosed(11.6%in

ISDUETO

CANCER

allcases)cancerandtheleadingcauseofdeath(18.4%ofalldeaths)

fromcancer.Breastcancer,coloncancer,prostatecancer,stomach

2018

2040

cancerandlivercancerarecancerswithtopincidencesand

18.1mil

29.4mil

mortalities.Figure2showsthetop10typesofcancersintheworld,

ofwhichlungcancerandbreastcancerarementionedinthis

Cancercasesperyearglobally

handbook.

Figure1.Globalcancerburdens[1]

Incidence

11.6%

Lung

Thetraditionalhallmarksofcancerincludesustainingproliferative

11.6%

signaling,evadinggrowthsuppressors,resistingcelldeath,enabling

36.7%

Breast

replicativeimmortality,inducingangiogenesis,andactivating

Other

invasionandmetastasis.Nowadays,reprogrammingofenergy

10.2%

metabolismandevadingimmunedestructionisincluded.Inthis

Colorectum

handbook,somehottopicsincancersuchascancermetabolism,

3%

7.1%

cancerimmunotherapy,andcancerstemcellsareinvolvedand

Bladder

Prostate

relatedsmallmoleculechemicalsarelistedpartially.

3.1%

3.2%

5.7%

Thyroid

4.7%Stomach

Cervixuteri

3.2%

Liver

Oesophagus

Contents

18.1millioncases

CancerMetabolism

3

Mortality

CancerImmunotherapy

5

18.4%

29.3%

Lung

CancerStemCells

8

Other

9.2%

Colorectum

CancerPathways

9

3.2%

8.2%

Leukaemia

NSCLC

10

3.3%

Stomach

Cervixuteri

8.2%

3.8%

4.5%

6.6%Liver

BreastCancer

12

ProstatePancreas5.3%

Breast

Oesophagus

PROTACs

13

9.6milliondeaths

Antibody-DrugConjugates(ADCs)

15

Figure2.Theleadingcancertypesin2018[1]

2

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

CancerMetabolism

Cancerhasdifferentmetabolicpatternfrommostnormaltissues.Metabolictargetsofaberrantmetabolismcancercellspresentnewtherapeuticperspectives,andagreatprocesshasbeenmade.

Warburgeffectoraerobicglycolysisindicatesthatcancercellsconsumetremendousamountsofglucoseandmetabolizethemintolactatedespitethepresenceofoxygen.Lactateandpyruvategeneratedinaerobicglycolysiscanguaranteethesufficientbiomassforlipids,nucleotidesandaminoacidsofproliferatingcancercells.What’smore,ahighleveloflactateoffersanacidicimmunosuppressiveenvironmentforcancercells.Enzymesandsignalingpathwaysinvolvedinglycolysissuchasglutaminase,PI3K/AKT/mTORsignalingpathway,isocitratedehydrogenase(IDH)arepromisingtargetsforcancertherapy.

Exceptforcarbohydratemetabolism,themetabolismsofothermoleculesareabnormalincancercells.Becauseoftheabsenceoftheabilitytosynthesizesomenon-essentialaminoacids,anextrasupplyofthemisnecessaryforthesurvivalofcancercells.Targetingthesemoleculessuchasphosphoglyceratedehydrogenase(PHGDH)inaminoaciddependenceispotentialcancertherapy.Themajorityofcancercellscansynthesizelipiddenovo,whichensuresacontinuoussupplyofrawmaterialstobuildacellmembrane.Acetyl-coAcarboxylase(ACC)andfattyacidsynthase(FASN)arekeyenzymesinlipidsynthesisandmightbeeffectivetargetsofcancertherapy.Nucleotidemetabolismisalsohyperactiveinmanycancercells.Infact,theclinicalsuccessofantimetabolitechemotherapiesfortreatingcancerbenefitsfromtheincreaseddemandofnucleotidesfornucleotidebiosynthesisandDNAreplication.

ADI-PEG

Arginine

Lactate

Metformin

Glucose

Metformin

Salicylates

KRAS

AMPK

LKB1

AT

MCT1

HIF1α

GLUT1

Pl3K/AKT

Arginine

AZD3965

mTOR

Glucose

HK

Nucleotide

G6P

Ribose-5p

Proteinsynthesis

HIF1α

synthesis

GPNA

2NADP+

2NADPH

F6P

Aminoacid

Asparagine

Gossypol

PFK

Serine

Glycine

and

Glutamine

SLC1A5

Glutamine

FX-11

3PGPHGDHPSATPSPH

nucleotide

Galloflavin

NAD+NADHGlutamate

α-KG

synthesis

MYC

AOA

TA

LDHA

MYC

NADH

NADPH

NADP+

Lactate

Pyruvate

Fatty-acid

Glutathione

Glutamate

Citrate

Acetyl-CoA

synthesis

Aspartate

NAD+

NADH

ACLY

ACC

FASN

Cysteine

EGCG

HMG-CoA

Glycine

DCA

PDK

PDH

AMPKPl3K/AKT

C75

reductase

Orlistat

Nucleotidesynthesis

StatinsMetformin

Cholesterol

TA

AOA

Mevalonate

Salicylates

synthesis

Ketoacids

Aminoacids

Acetyl-CoA

GPNA

Proteinsynthesis

Glutathione

EGCG

Nucleotide

α-KG

Polyamines

Citrate

synthesis

DNAmethylation

GDH

Methionine

MT

Methionine

OAA

α-KG

GlutamateCB-839

TA

BPTES

Methioninase

TCACycle

AOA

GLS

MYC

Proteinsynthesis

Malate

Succinyl-CoA

Mitochondrion

Fumarate

Glutamine

Glutamine

SLC1A5

Glutamine

Figure3.Mainmetabolicpathwaysderegulatedincancersandcorrespondingtargetingdrugs[2]

3

MCE

MasterofBioactiveMolecules

Cat.No.

ProductName

HY-17394

Cisplatin

HY-B0627

Metformin

HY-12248

Telaglenastat(CB-839)

HY-100017

BAY-876

HY-18767

Ivosidenib(AG-120)

HY-19992

3-Bromopyruvicacid

HY-135841

CM10

HY-A0210

Cerulenin

HY-120394

TVB-3166

HY-Y0445A

Sodiumdichloroacetate

HY-119502

Camalexin

HY-122312

BAY-8002

Compounds

Description

Anantineoplasticchemotherapyagentbycross-linkingwithDNA.

Themostcommonlyprescribeddrugfortype2diabetesandinhibitsgrowthofcertaintypesofcancer.

Afirst-in-classglutaminase1(GLS1)inhibitor.

AnorallyactiveGLUT1inhibitorandinhibitsglycolyticmetabolismandovariancancergrowth.

AnorallyactiveIDH1inhibitorforAMLtherapy.

AhexokinaseIIinhibitor,andaneffectiveantitumoragentonthehepatomacells.

AnALDH1Ainhibitor.Regulatesmetabolismandhasanti-canceractivity.

Thebestknownnaturalinhibitoroffattyacidsynthase(FASN).

AFASNinhibitorandinhibitsin-vivoxenografttumorgrowth.

AmetabolicregulatorthatincreasesROSgenerationandpromotescancercellapoptosis.

InducesROSproduction.Anticanceractivities.

AnorallyactiveinhibitorofMCT1.Anti-tumoractivity.

CompoundScreeningLibraries

Cat.No.:HY-L012

Metabolism/ProteaseCompoundLibrary

AuniquecollectionofMetabolism/Protease-relatedsmallmoleculesthatactsasausefultoolfordrugdiscoveryofmetabolism-relateddiseases.

Cat.No.:HY-L058

GlycolysisCompoundLibrary

Auniquecollectionofglycolysis-relatedsmallmoleculesforglucosemetabolismresearchandanti-cancerdrugdiscovery.

Cat.No.:HY-L064

GlutamineMetabolismCompoundLibrary

Auniquecollectionofglutaminemetabolism-relatedsmallmoleculestargetingthemainlyproteinsandenzymesinvolvedinglutaminemetabolismpathway.

4

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

CancerImmunotherapy

Theimmunesystemcandistinguishbetweenselfandnon-self.Tumorcellshavetheabilitytoavoidrecognitionandeliminationbytheimmunesystem,allowingmalignantcancersprogression.Overthelastfewdecades,tremendousprogresshasbeenmadeintheunderstandingofimmuneescapemechanismsoftumors,whichinturnoffersstrategiesofimmunotherapyforcancer.Immunotherapyforcancerhasattractedincreasinginterestandgainedimpressiveclinicalbenefits.Avarietyofproteins/receptorsarenowbeinginvestigatedaspotentialtargetsforcancerimmunotherapy,inwhichimmunecheckpointsandtumormicroenvironment(TME)isoutstanding.

Immunecheckpointsareregulatorsoftheimmunesystemincludingstimulatorycheckpointmoleculesandinhibitorycheckpointmolecules.StimulatorycheckpointmoleculessuchasCD28,TCRarenecessaryforactivationofTcells,andinhibitorycheckpointmoleculessuchasCTLA4andPD1cancauseimmunosuppression.Targetingtheinhibitorycheckpointsusingantibodiesorsmallmoleculesisapromisingtherapyforcancertreatment.

Activation Anergy Exhaustion

APC

Anti-CTLA-4

MHC

CD80/86

TCR CD28CTLA-4

T-cell

+

+

+

-

Perforin

Granzymes

IFN-γ

IL-2

Proliferation

Proliferation

Effectorcytokines

Effectorcytokines

Cytotoxicity

Cytotoxicity

Figure4.SchematicofmechanismofCTLA-4andPD-1[3]

Anti-PD-1

Anti-PD-L1

PD-1

PD-L1

+ +PD-L2

Tumorcell

Proliferation

Effectorcytokines

Cytotoxicity

Thetumormicroenvironment(TME)isthecellularenvironmentinwhichthetumorexists,includingsurroundingblood

vessels,theextracellularmatrix(ECM),othernon-malignantcells,

TAM

CAF

andalsosignalingmolecules.Researchershave

Monocytes

recognizedthatnormalcellsinTMEarestromalcells,

Growthfactors

cancerassociatedfibroblasts(CAFs),immunecells,

endothelialcells,etc.ExceptfortoxicTcells,Bcells,

TC

Tumor-secreted

therearealsoregulatoryTcells,tumor-associated

T

exosomes

macrophages(TAMs),myeloidderivedsuppressor

Immune

B

Hypoxia

cells(MDSCs).Thegrowthfactorssecretedby

cells

Inflammation

EC

stromalcellsandCAFcannotonlypromotegrowth

andsurvivalofmalignantcellsbutalsofunction

ECM

MSC

asnegativeregulatorsoftheimmuneresponse.

collagen

Figure5.Diagramoftumormicroenvironment[4]

5

MCE

MasterofBioactiveMolecules

AllthecomponentssynergizeanimmunosuppressiveTME.MoleculesassociatedwithTMEsuchascytokinereceptors,metabolicenzymesarecriticaltargetsincancerimmunotherapy.ThesetargetsincludeRORγt,Chemokinereceptor(CXCR),Sting,IDO,TLR,etc.

Cat.No. ProductName

HY-P9901 Ipilimumab

HY-P9904 Atezolizumab

HY-19745 BMS-202

HY-102011 BMS-1166

HY-104037

Cintirorgon(LYC-55716)

HY-126321

RORγtagonist1

HY-19855

AZD-5069

HY-119339

SX-682

HY-13226

Galunisertib(LY2157299)

HY-19928

Vactosertib(EW-7197)

HY-10964

Vadimezan(DMXAA)

HY-130115

IACS-8803

HY-130116

IACS-8779

HY-16724

Indoximod(NLG-8189)

HY-15689

Epacadostat

HY-18770B

Navoximod(GDC-0919)

HY-101560

Linrodostat(BMS-986205)

Compounds

Description

AhumanizedmonoclonalIgG1κantibodyagainstCTLA-4.ApprovedbyFDAforthetreatmentofmelanoma.

AselectivehumanizedmonoclonalIgG1antibodyagainstPD-L1.

ApprovedbyFDAforthetreatmentofNSCLC.

ApotentPD-1/PD-L1complexinhibitorwithantitumoractivity.

ApotentPD-1/PD-L1checkpointinhibitorthatantagonizestheinhibitoryeffectofPD-1/PD-L1immunecheckpointonTcellactivation.

Afirst-in-classRORγagonistthatdecreasestumorgrowth,andimprovessurvival.

Apotent,orallybioavailableRORγtagonistforcancerimmunotherapy.

ApotentCXCR2antagonist,usedforcancerstudy.

AnorallybioavailableinhibitorofCXCR1andCXCR2.SX-682enhancesTcellactivationandantitumorimmunity.

AselectiveTGF-βRIkinaseinhibitorwithanti-tumoractivity.

AnorallyactiveALK5inhibitorandhaspotentlyantimetastaticactivityandanticancereffect.

Thetumorvasculardisruptingagent.AnagonistofSTING.

ApotentSTINGagonistwithrobustsystemicantitumorefficacy.

ApotentSTINGagonistwithrobustsystemicantitumorefficacy.

AnIDOpathwayinhibitorwithanti-tumoractivity.

AselectiveIDO1inhibitorfortreatingadvancedcancer.

ApotentIDOpathwayinhibitorforsolidtumors.

AselectiveIDO1inhibitorwithpotentpharmacodynamicactivityinadvancedcancers.

6

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

Compounds

Cat.No.

ProductName

Description

HY-101111

PF-06840003

AselectiveIDO-1inhibitorandinhibitstumorgrowth.

HY-101978

CPI-444

AselectiveA2ARantagonist,whichinducesantitumorresponses.

HY-101980

AZD4635

AnorallyactiveA2ARantagonistwithanti-tumoractivity.

HY-101979

Numidargistat(CB-1158)

Anorallyactiveinhibitorofarginase.Immuno-oncologyagent.

HY-N0242

Fraxinellone

APD-L1inhibitorforcancertreatment.InhibitsHIF-1αprotein

synthesiswithoutaffectingHIF-1αproteindegradation.

HY-P9902

Pembrolizumab

Ahumanizedantibodythatinhibitstheprogrammedcelldeath1

(PD-1)receptor,usedincancerimmunotherapy.

HY-125506

NP-G2-044

Apotent,orallyactivefascininhibitorthatblockstumormetastasis

andincreasesantitumorimmuneresponse.

HY-136927

MSA-2

Apotentandorallyavailablenon-nucleotideSTINGagonistthat

inducestumorregressionwithdurableantitumorimmunity.

HY-136198

SRX3207

Anorallyactiveandfirst-in-classdualSyk/PI3Kinhibitorthatrelieves

tumorimmunosuppression.

HY-126147

J22352

APROTAC-likeandhighlyselectiveHDAC6inhibitorthatinduces

anticancereffects.

HY-129601

MYCi975

AnorallyactiveMYCinhibitorthatdisruptsMYC/MAXinteraction.

Anti-tumorefficacy.

HY-119367

ODM-203

ApotentFGFRandVEGFRinhibitorthatexhibitsstronganti-tumor

activityandinducesanti-tumorimmunity.

HY-16961

Sitravatinib

Anorallybioavailablereceptortyrosinekinase(RTK)inhibitorthat

showspotentsingle-agentantitumorefficacy.

HY-123291

SM-276001

AselectiveTLR7agonistinducesantitumorimmuneresponses.

CompoundScreeningLibrary

Cat.No.:HY-L031

SmallMoleculeImmuno-OncologyCompoundLibrary

AuniquecollectionofbioactivetumorimmunologycompoundsthattargetsomeimportantcheckpointssuchasPD1/PD-L1,CXCR,STING,IDO,TLR,etc.

7

MCE

MasterofBioactiveMolecules

CancerStemCells

Heterogeneityisoneofthemostrelevantfeaturesofcancercellswithindifferenttumortypesandisresponsiblefortreatmentfailureandrecurrence.Cancerstemcells(CSCs)areapopulationofcellswithstemcellpropertiesthatareconsideredtobetherootcauseoftumorheterogeneitybecauseoftheirabilitytoself-renewalanddifferentiateintoallofcancercelltypes.

CSCsaregenerallyconsideredinsensitivitytotraditionalchemotherapydrugs.Conventionaltherapykillsnon-CSCsbutleavesCSCsuntouched,leadingtotumorrelapse.KillingtheCSCsmayresultineventualtumoreradication(Figure6).ForCSCtherapy,promotingCSCsdifferentiationintonon-CSCs,inhibitingself-renewalpropertyofCSCs,CSCsmicroenvironmentispromisingtargets.What’smore,moleculesorpathwaysdirectlyrelatedtodrugresistanceofCSCssuchasmultidrugresistanceproteinsandanti-apoptoticpathwayshavealsobeenexplored.

CSCNon-CSCStromalcell

Time

Time

Cure

AblationofCSCs

Tumorregression

Time

Time

Relapse

Ablationofnon-CSCs

Tumorregression

Figure6.DiagramofcancerrecurrencebasedonCSCs[5]

Tothedate,themostexploitedsignalingpathwaysassociatedwiththeself-renewalofCSCsaretheHedgehogsignalling,NotchsignallingandWnt/β-cateninsignalingpathways.AsforpromotingthedifferentiationofCSCs,bonemorphogenicprotein(BMP)signalingandP13K/mTORsignalingareamongthemoststudiedsignalingpathways.

Compounds

Cat.No.

ChemicalName

Description

HY-10440

Vismodegib(GDC-0449)

Ahedgehogpathwayinhibitorforadvancedbasalcellcarcinoma.

HY-135145

CB-103

Afirst-in-classnotchpathwayinhibitorwithanti-tumoractivity.

HY-15531

Venetoclax(ABT-199)

ApotentBcl-2inhibitorandeffectivelytargetsCSCpopulation.

HY-100431

IMR-1

ANotchinhibitorandinhibitstumorgrowth.

HY-15721

FH535

AninhibitorofWnt/β-cateninandPPAR.Anti-tumoractivities.

HY-12020

TW-37

ApotentBcl-2inhibitorthatactsasananticolorectalcanceragent.

HY-16591

Birinapant(TL32711)

ApotentXIAPandcIAP1antagonist.Inductionoftumorcelldeath.

HY-12289

Defactinib(VS-6063)

AFAKinhibitorwithantiangiogenicandantineoplasticactivities.

HY-13917

PND-1186

ApotentFAKinhibitorwithanti-canceractivity.

CompoundScreeningLibrary

Cat.No.:HY-L017

StemCellSignalingCompoundLibrary Auniquecollectionofcompoundsforstemcellsignalingresearch.

8

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

CancerPathways

Notch,Hippo,Hedgehog,Wnt,andTGF-β/BMP/FGFsignalingpathwaysarehighlyconservedcellsignalingsystemspresentinalmostallmulticellularorganisms.Theyarenetworksthatactcoordinatelytoplaycrucialrolesincellprolifera-tion,apoptosis,differentiation,andfinallyinorgandevelopment.Disruptionsofgenesinonepathwaycanhaveeffectsinrelatedpathwaysandmayresultincancer.

Compounds

Cat.No.

ProductName

Description

HY-101275

EMTinhibitor-1

AninhibitorofofHippo,TGF-β,andWntsignalingpathwayswith

antitumoractivities.

HY-B0146

Verteporfin(CL318952)

InhibitstheHippopathwayandblocksthetranslocationofYAP/TAZinto

thenucleus,thusinhibitingcancercellgrowthandsurvival.

HY-12419

BMS-983970

Anoralpan-Notchinhibitorforthetreatmentofmultiplecancers.

HY-N0133

Tangeretin(NSC53909)

ANotch-1inhibitorwithanti-tumoractivity.

HY-16582A

Sonidegib(Erismodegib)

ApotentSmoantagonistforlocallyadvancedbasalcellcarcinoma.

HY-10440

Vismodegib(GDC-0449)

AHedgehogpathwayinhibitor.ApprovedbyFDAforthetreatmentof

locallyadvancedbasalcellcarcinoma.

HY-18959

CWP232228

AhighlypotentWnt/β-cateninsignalinginhibitorthatinhibitsthegrowth

ofbreastandlivercancerstemcells(CSCs).

HY-103021

LY3200882

AhighlyselectiveTGF-βR1(ALK5)inhibitorthatactsasanimmune

modulatoryagent.

HY-101568

Roblitinib(FGF-401)

AhighlyselectiveFGFR4inhibitorwithanti-tumoractivity.

HY-N2112

GlaucocalyxinA

InhibitsGLI1viaregulatingPI3K/Aktpathway.Antitumoreffect.

CompoundScreeningLibraries

Cat.No.:HY-L018

TGF-beta/SmadCompoundLibrary

AuniquecollectionofTGF-beta/SmadsignalingpathwaycompoundsusedforTGF-beta/Smad-relateddrugscreeninganddiseaseresearch.

Cat.No.:HY-L020

Wnt/Hedgehog/NotchCompoundLibrary

AuniquecollectionofWnt/Hedgehog/Notchsignalingpathway-relatedsmallmoleculesusedforstemcellresearchandanti-cancerdrugscreening.

9

MCE

MasterofBioactiveMolecules

NSCLC

Asmentionedabove,lungcanceristhemostfrequentlydiagnosedcancerandtheleadingcauseofcancerdeathintheworld.Lungcancersareagroupofdistinctdiseaseswithcellularandgeneticheterogeneity.Approximately85%oflung

KEY

EGFR

ERBB2/3

MET

FGFR1,2,3

ALK

RET

ROS

Activated

27%

<9%

3%

2-4%

7%

7%,3%,2%

<8%

1%

2%

Inactivated

LUAD

PTEN

KRAS

NRAS

RASA

3%

15%

PIK3CA

32%

3%

<1%<1%

4%

LUSC

PIK3R1

4%16%

HRAS

RIT1

NF1

<1%

<1%

3%

2%

11%

11%

STK11

AKT1

AKT2

AKT3

17%

2%

1%

<1%

4%

16%

BRAF

7%

4%

AMPK

TSC1/2

3%

3%

MAP2K1

<1%

<1%

MTOR

CDKN2A

43%

70%

Proliferation,cellsurvival,translation

KEAP1

CUL3

MDM2

ATM

CCND1

CDK4

CCNE4

19%

12%

<1%

7%

8%

9%

4%

7%

3%

NFE2L2

TP53

RB1

3%

19%

46%

90%

7%

7%

OxidativestressresponseProliferation,cellsurvival

Cellcycleprogression

cancerisnon-smallcelllungcancer(NSCLC),ofwhichlungadenocarcino-ma(LUAD;~50)andlungsquamouscellcarcinoma(LUSC;~40)arethemostcommonsubtypes.Aseriesofgeneticmutationsareidentifiedinlungcancer,suchasKRAS,BRAF,EGFR,TP53,AKT,etc.Mostofthemarepromisingtherapeutictargetsforlungcancer.

Figure7.TargetablemutationsinvolvedinLUADandLUSC[6]

Compounds

Cat.No.

ChemicalName

Description

HY-50896

Erlotinib

AdirectlyactingEGFRinhibitorforthetreatmentofNSCLC.

HY-50895

Gefitinib

AselectiveandorallyactiveEGFRinhibitorfortreatmentofNSCLC.

HY-15772

Osimertinib

AnirreversibleandmutantselectiveEGFRinhibitorforthetreatment

ofEGFRT790MNSCLC.

HY-50878

Crizotinib

AnorallybioavailableALKandc-Metinhibitorforthetreatmentof

advancedALK+/ROS1+NSCLC.

HY-13011

Alectinib

HY-114277

Sotorasib(AMG-510)

HY-130149

Adagrasib(MRTX849)

AnorallyavailableALKinhibitorforthetreatmentofadvancedALK+NSCLC.

ThefirstKRASG12CinhibitorinclinicaldevelopmentandleadstotheregressionofKRASG12Ctumors.

Amutation-selectivecovalentinhibitorofKRASG12Cwithpotentialantineoplasticactivity.

10

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

Compounds

Cat.No. ChemicalName Description

HY-130260

KRASinhibitor-4

HY-19980A

PRIMA-1

HY-122054

BPK-29

ApotentKRASinhibitoranddevelopedasananticanceragent.

Amutantp53reactivatorwithanti-tumoractivity.

AspecificligandthatdisruptsNR0B1-proteininteractions.Impairsanchorage-independentgrowthofKEAP1-mutantcancercells.

HY-136173

TNO155

Anorallyactiveallostericwild-typeSHP2inhibitorforthestudyof

RTK-dependentmalignancies,especiallyadvancedsolidtumors.

HY-112823

Almonertinib

Anorallyavailable,irreversibleEGFRinhibitorwithhighselectivityfor

EGFR-sensitizingandT790Mresistancemutations.

HY-136174

RBN-2397

Apotent,accrossspeciesandorallyactiveNAD+competitivePARP7

inhibitorforthestudyofadvancedormetastaticsolidtumors.

HY-123986

CTPI-2

Athird-generationmitochondrialcitratecarrierSLC25A1inhibitor.

HY-116000

Glumetinib

Ahighlyselective,orallybioavailable,ATP-competitivec-Metinhibitor.

Antitumoractivity.

HY-131067

EMI56

ThederivativeofEMI1,displaysgreaterpotencytowardmutantEGFR

thanEMI1.InhibitsEGFRtriplemutants.

HY-12215

Lorlatinib

Aselective,orallyactive,brain-penetrantandATP-competitive

ROS1/ALKinhibitor.Anticanceractivity.

HY-131066

EMI48

ThederivativeofEMI1,displaysgreaterpotencytowardmutantEGFR

thanEMI1.InhibitsEGFRtriplemutants.

HY-19637

SW044248

Anon-canonicaltopoisomeraseIinhibitor,andselectivelytoxicfor

certainNSCLCcelllines.

HY-112299

TAS6417

AnEGFRinhibitorforNSCLC.

HY-19730

Olmutinib

AnorallyavailableandirreversiblethirdEGFRinhibitorthatbindstoa

cysteineresiduenearthekinasedomain.UsedforNSCLC.

CompoundScreeningLibrary

Cat.No.:HY-L025

Anti-CancerCompoundLibrary

Auniquecollectionofbioactiveanti-cancercompoundsthattargetkinases,cellcyclekeycomponents,tumorigenesisrelatedsignalingpathways,etc.

11

MCE

MasterofBioactiveMolecules

BreastCancer

Justlikelungcancer,breastcancerisalsoaveryheterogeneousdiseasewithdistinctclinicalimplicationsanddifferent

molecularsubtypes.Themajorsubtypesofbreastcancer

areapproximatedbythejointexpressionofthreetumormarkers:

HER2

estrogenreceptor(ER),progesteronereceptor(PR),

andhumanepidermalgrowthfactorreceptor2(HER2).

Asshowninfigure8,thefourmainsubtypesofbreastcancer

HER2Enriched

LuminalB

aredescribedasLuminalA(HR+/HER2-),LuminalB(HR+/HER2+),

HR-HER2+

HR+HER2+

HER2enriched(HR-/HER2+),andbasal-like(triple-negative,

HR

HR-/HER2-),inwhichHRrepresentshormonereceptorincludingER

andPR[7].ExceptforthedifferentexpressionpatternofHRand

Basallike

LuminalA

HR-HER2-

HR+HER2-

HER2,therearealsomanygeneticmutations(suchasPTEN,BRCA1,

BRCA2,TP53,XRCC2,XRCC3,ATM,CHEK2,PALB2,RAD51,XPD)

havebeenimplicatedinbreastcancer.Targetingtherelatedproteins

Figure8.SubtypesofbreastcanceraccordingtoHR/HER2[7]

hasaroleinbreastcancerresearchandmanagement.

Compounds

Cat.No.

ProductName

Description

HY-P9907

Trastuzumab

Ahumanizedmonoclonalantibodyforthetreatmentofmetastatic

HER2+breastcancer.

HY-P9912

Pertuzumab

Ahumanizedmonoclonalantibodyforthetreatmentofmetastatic

HER2+breastcancer.

HY-13757A

Tamoxifen

AnorallyactiveERmodulator.ApprovedbyFDAforthetreatment

ofbreastcancer.

HY-119377

UPGL00004

AnallostericGACinhibitorthatinhibitstheproliferationofhighly

aggressivetriple-negativebreastcancercelllines.

HY-10162

Olaparib

AnorallyactivePARPinhibitor.ApprovedbyFDAforthetreatment

ofBRCA+/HER2-breastcancer.

HY-124691

D-I03

AselectiveRAD52inhibitorthatsuppressesgrowthofBRCA1-and

BRCA2-deficientcells.

HY-50767

Palbociclib

AselectiveCDK4andCDK6inhibitorthathasthepotentialforER+/HER2-

breastcancerresearch.

HY-N0656A

(+)-Usnicacid

InhibitsmTORC1/2.Anti-canceractivity.

HY-15842

SF1670

AspecificPTENinhibitorfortheresearchofbreastcancer.

HY-10029

Nutlin-3a

InhibitsMDM2-p53interactionsandhasthepotentialforthestudy

ofovariancarcinomas.

12

www.MedChemE

Inhibitors ? ScreeningLibraries ? Proteins

PROTACs

PROTACsorPROteolysisTArgetingChimericMoleculesarestructurallycomprisedoftworecognitionmotifslinkedbyalinker.Onerecognitionmotifisasmallmoleculeligandfor

theproteinofinterest,theotherrecognizes

aspecificE3ligase.APROTACcanrecruitanE3ligasetoatargetproteinandresultinthedegradationof

theproteinthroughubiquitination

Ub

proteasomepathway.PROTACsare

E3

anemergingandpromisingapproachfor

E3ligase

thedevelopmentoftargetedtherapydrugs

andmanyPROTACswithhighpotency

havebeenfrequentlyreported.

Ligandforr