table of contents alphabetical index - lubio · table of contents alphabetical index pi3k hdac raf...

Table of Contents Alphabetical IndexPI3KHDACRafVEGFRMEKJAKAktPARPmTORCDKBTKc-MetEGFRBcl-2TGF-beta/SmadProteasomeGamma-secretaseGSK-3Androgen ReceptorBcr-AblROCKAurora KinaseDNA/RNA SynthesisFGFRHSP (e.g. HSP90)Hedgehog/SmoothenedSrcp38 MAPKPLKSykMicrotubule AssociatedTopoisomeraseIGF-1RPDGFRCFTRWnt/beta-cateninHER2TNF-alphaPKCChkALKATM/ATRPDEFLT3SirtuinIAPMdm2

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1011121314151617181920212223242526272829303132333435363738394041424344454647

AktALKAndrogen ReceptorATM/ATRAurora KinaseBcl-2Bcr-AblBTKCDKCFTRChkc-MetDNA/RNA SynthesisEGFRFGFRFLT3Gamma-secretaseGSK-3HDACHedgehog/SmoothenedHER2HSP (e.g. HSP90)IAPIGF-1RJAKMdm2MEKMicrotubule AssociatedmTORp38 MAPKPARPPDEPDGFRPI3KPKCPLKProteasomeRafROCKSirtuinSrcSykTGF-beta/SmadTNF-alphaTopoisomeraseVEGFRWnt/beta-catenin

741194222142011103540122313244417182

26372546336

475

319

288

43341

3929163

214527301538324

36

A

B

C

DEF

G

H

I

JM

P

R

S

T

VW

For detailed product information, please visit us online: www.selleckchem.com

Kinases Class II Class I

PTENClass IIIPhosphatases

Structuraldomains

Vesicular transport

lon channels,

amino acidtransport

Growth, Survival, Proliferation,Differentiation and Migration/motility

Pl Pl(3)P Pl(4,5)P2

EEA1

Rabip4

FAB1

p40phox

SGK3

TAPP1

GAPS

Rho

ARF

GEFS

DAPP GAB1/2

ITKSNX3SNX17

Rabenosyn-5

BTK inhibitorsPCI-32765GDC-0834

Rac inhibitorNSC 23766

PDK-1 inhibitorsBX-912BX-795

OSU-03012PHT-427

Growth factors, GPCRs

Tyrosine Kinases,GPCRs,

Oncogenes

BEZ235LY294002GDC-0941

Selective PI3K inhibitorsBYL719(PI3Kα)

GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

SHIPPl(3,4,5)P3 Pl(3,4)P2

Akt

PI3K PI3K

BTK

Rac

PDK1

FYVE domain PX domain PH domain

PI3K

S1105 LY294002

S1065 GDC-0941 Phase 2

S2226 CAL-101(Idelalisib)

Phase 3p110δ

PI3Kα

p110β

S2247 BKM120(NVP-BKM120)

Phase 4

S2814 BYL719 Phase 1/2

S1169 TGX-221

S1268 IC-87114

Phase 1/2a

PI3Kδ

PI3Kγ S1410 AS-605240

p110β S8002 GSK2636771

Phase 2PI3Kδ/γ S7028 IPI-145(INK1197)

2008

2007

2008

2010

2011

2012

2007

2003

2005

2012

2012

S1009 BEZ235(NVP-BEZ235)

Phase 2p110α p110γ p110δ p110β4 5 7 75IC50(nM)

p110α p110δ p110βIC50(μM) 0.5 0.57 0.97

p110α p110δ p110β p110γIC50(nM) 3 3 33 75

p110δ2.5IC50(nM)

p110α p110β p110δ p110γIC50(nM) 52 166 116 262

β γ75 29

α5IC50(nM)

5p110β

IC50(nM)

δIC50(μM) 0.5

γ8

α60

β270

δ300IC50(nM)

PTEN null cell lines (human prostate adenocarcinoma PC-3)

EC50(nM) 36

PTEN null cell lines (breast cancer HCC70)72

δIC50(nM) 1Ki(pM) 23

γ50243

PI3K

PI3K

PI3K

PI3K

PI3K

PI3K

PI3K

PI3K

PI3K

PI3K

Cat.No. Product Name Information Selectivity Clinical Trial

Discov

ery

1

PI3K inhibitors

CCT128930(Akt2)

Pan-Akt inhibitorsMK-2206

GSK690693GDC-0068

Selective Akt inhibitorsA-674563(Akt1)

HDAC

Ca2+

MHCII

TCR

PLC

PKD1

c-Jun

Vav

Rho

LAT

PLC-γ

IFNγ IFNα/β

IFNARIFNGR

TLR

CaMK

MTA

HAT

TRIFTRAM

TRIF

Mal

MyD88MyD88

HAT

MKP-1

ATF3

HATs

HATs

p50 p65

p50 p65

p50 p65

MTA2

Other mediators(eg,Edn-1,MMP9)

IfnβHATs

MTA1

p50 p65

p50 p65

14-3-3

PLZF

GRDeacetylation

IRF

CIITA

DNA binding

PKD MEF

MEF

ll-10

PKD3

Chromatinregulation

Neural SignalingGPCRVEGF

VEGFR

Cytokines(lL-6,TNF-α,IFN-β)Inflammatory mediators:

Chemokines(Ccl2,Ccl7,Cxcl10)

HDAC

HDACⅡ

HDAC

HDAC

HDAC4

HDAC9

HDAC7

HDAC5

HDAC

HDACs

HDACs

HDACs

HDAC1

STAT

HDAC3

HDAC2

HDAC1

HDAC1

HDAC8

HSP90

HDAC9

HDAC1

p50Lys314/315 Lys221

Lys122/123 Lys310

AC

AC

AC

AC AC

AC

AC

17-AAGAUY922

Ganetespib17-DMAG

GeldanamycinHSP70 inducer

Elesclomol

HSP90 inhibitors

Pan-VEGFR inhibitors

Selective VEGFR inhibitors

Nintedanib Pazopanib

Axitinib

ZM 306416(VEGFR1)Cabozantinib(VEGFR2)SAR131675(VEGFR3)

ζ ζ

HDAC1

HDAC2

FG-4592IOX2

2-Methoxyestradiol

HIF inhibitors

HDAC11

p38

HATs

HDACs

EntinostatVorinostat

PanobinostatSelective HDAC inhibitors

CI994(HDAC1)Rocilinostat(HDAC6)PCI-34051(HDAC8)

Pan-HDAC inhibitors




Pan-HDAC inhibitors

Fludarabine(STAT1)NSC 74859(STAT3)

Niclosamide(STAT3)

Selective STAT inhibitors

AZD7762PF 477736

Selective Chk inhibitorsLY2603618(Chk1)CHIR-124(Chk1)

SCH 900776(Chk1)

Pan-Chk inhibitors

JNJ 26854165RITA

Tenovin-1p53 inhibitor

Pifithrin-α

p53 activators

HDAC6

IKK-16BAY 11-7082

Selective IKK inhibitorsTPCA-1(IKKβ)

IMD 0354(IKKβ)

Pan-IKK inhibitors

GR

HDAC6

HSP90

CHK

ROCK

IκBα

IκBα

IκBα

IκBα

p53

HIF-1α

p53AC

HIF-1αAC

S1030 Panobinostat (LBH589)

S1053 Entinostat (MS-275)

Phase 2

S3020 Romidepsin (FK228)

Phase 2

S1045 Trichostatin A (TSA)

Phase 3

S2012 PCI-34051

Phase 3S2818 CI994 (Tacedinaline)

S7229 RGFP966 HDAC3

HDAC6S8001 Rocilinostat(ACY-1215)

1998

2008

1999

2002

2001

2008

2008

2013

2012

2000

S1047 Vorinostat(SAHA, MK0683)

Phase 3

Phase 2

HDAC1 HDAC310 20IC50(nM)

HDAC (MOLT-4 cells)

HDAC (Reh cells)

IC50(nM) 5 20

HDAC1 HDAC3IC50(μM) 0.51 1.7

HDAC136

HDAC247IC50(nM)

HDACIC50(nM) ~1.8

HDAC810IC50(nM)

0.57HDAC1

IC50(μM)

HDAC3IC50(nM) 80

HDAC65IC50(nM)

exceptHDAC8

HDAC8

HDAC1

S8043 Scriptaid Scriptaid is an inhibitor of HDAC. It shows a greater effect on acetylated H4 than H3.

2


Discov

ery

HDAC inhibitors

P

P

P

P

SB 203580SB 202190

VX-745Selective p38 inhibitors

BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

ThiazovivinGSK429286A

Selective ROCK inhibitorsY-27632(ROCK1)Fasudil(ROCK2)

Pan-ROCK inhibitors

Raf

3

S1040 Sorafenib Tosylate

S2807 Dabrafenib (GSK2118436)

Phase 3

S1152 PLX-4720

B-Raf

S2161 RAF265(CHIR-265)

Phase 2

S2746 AZ 628 Phase 4

S2220 SB590885

S2720 ZM 336372

Phase 1/2

C-Raf

S8015 CEP-32496

2010

2004

2009

2008

2008

2007

2009

2006

1999

2012

S1267 Vemurafenib(PLX4032, RG7204)

Phase 2

Phase 2

B-RafV600E C-Raf Others31 48 MAP4K5 (KHS1),SRMS,ACK1

OthersVEGFR2,DDR2,Lyn,Flt1,FMS

OthersVEGFR2,PDGFRβ

OthersVEGFR2

IC50(nM)

C-Raf B-RafIC50(nM) 6 22

B-RafV600E B-Raf C-RafIC50(nM) 0.8 3.2 5.0

OthersB-Raf

B-RafV600E c-Raf-1Y340D/Y341D

13 6.7IC50(nM)

B-RafV600E B-Raf C-RafIC50(nM) 3-60

B-RafV600E

34

3-60 3-60

B-Raf105

C-Raf29IC50(nM)

S1104 GDC-0879 OthersC-Raf

B-RafV600E

0.13B-Raf0.13IC50(nM)

0.16B-Raf

1.72C-Raf

Ki(nM)

C-RafIC50(nM) 70

B-RafV600E

14B-Raf36

C-Raf39

OthersAbl-1,c-Kit,PDGFRβ,VEGFR2Kd(nM)

Cat.No. Product Name Information Selectivity Clinical TrialDisc

overy

Raf inhibitors

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors


Niclosamide(STAT3)


SCH772984ERK Inhibitor

JNJ 26854165RITA


Pifithrin-α

p53 activators

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors

StaurosporineSotrastaurinEnzastaurin

Pan-PKC inhibitors

IP3 Ca2+

Lin-1

RSK

SOS

ER81

GSK3

BAD IkBα

CREB

ATF4

c-Fosc-Jun

MNK

MNK1

MSK

Histone H3

AKT

ATF1

STAT3

p65

Paxillin

ASK1

TAO1,2

MLK2

MLK3

MLK1 DLKBax

Bid

DUSP1

Bcl2

MEKK1-4

MKK4,7

MEKK1-4

JNK1,2,3

MKK3,6

p38MAPKα,β

p38MAPKα,β

TAK1

Vinexin

MEF2

ATF1/2/6

SAP-1ELK-1

c-Jun

STAT4

JunD

HSF-1

ATF2

ETS-1

NFK3p53

p53

JNK

14-3-3

CREBeEF2K

MK2,3

MEK1,2

MAPK

MAP2K

Neurofilament

eIF4E

ERK1,2

ERK1,2

PKC Ras

CaMKPLCβ

Cytokines UVInflammatory Stress,LPS

GPCR

MAP3K

LPSCDC40TNFαRII

TCR

TAK1

Pan-Raf inhibitors

Selective Raf inhibitors

VemurafenibSorafenibPLX-4720

GDC-0879(B-Raf)GW5074(C-Raf)

Pan-MEK inhibitors

Selective MEK inhibitors

PD0325901GSK1120212U0126-EtOH

AZD6244(MEK1)BIX 02189(MEK5)

Pan-p38 inhibitors

Selective p38 inhibitors

SB 203580SB 202190

VX-745

BIRB 796(p38α)LY2228820(p38α)

JNK inhibitorsSP600125JNK-IN-8

A-Raf

B-Raf

Raf-1

CCT128930(Akt2)


GSK690693GDC-0068


Tideglusib(GSK-3β)TWS119(GSK-3β)

Pan-GSK3 inhibitorsCHIR-99021

CHIR-98014LY2090314

Selective GSK3 inhibitors

SB 216763

VEGFR

4

S1178 Regorafenib(BAY 73-4506)

S1035 Pazopanib HCl (GW786034 HCl)

Phase 2

S1010 Nintedanib (BIBF 1120)

Phase 2

Phase 2

S1046 Vandetanib (ZD6474)

Phase 1/2


Phase 2

Phase 3

S1101 Vatalanib (PTK787) 2HCl

S2897 ZM 336372

VEGFR2

VEGFR3

S2221 Apatinib

2011

2011

2008

2008

2002

2004

2000

2012

2011

2012

S1119 Cabozantinib(XL184, BMS-907351)

Phase 2

Phase 2

VEGFR2 Others0.035 c-Met,Ret,Kit,Flt3,Tie2,AXL

OthersPDGFRβ,Kit,RET,Raf-1

OthersPDGFR,FGFR,c-Kit,c-Fms

OthersFGFR1/2/3,PDGFRα/β

OthersEGFR

OthersRaf-1,B-Raf

OthersFlk,c-Kit,PDGFRβ

OthersSrc,Abl

IC50(nM)

VEGFR2 VEGFR1IC50(nM) 4.2 13

VEGFR346

VEGFR112

VEGFR36

VEGFR1 VEGFR2IC50(nM) 10 30

VEGFR347

VEGFR213

VEGFR313

VEGFR134

VEGFR177

VEGFR3660

VEGFR237

VEGFR10.33

IC50(nM)

VEGFR2IC50(nM) 40

VEGFR3110

VEGFR290IC50(nM)

IC50(nM)

IC50(μM)

VEGFR21

VEGFR323

IC50(nM)

IC50(nM)

VEGFR2

VEGFR1

S2842 SAR131675


overy

VEGFR inhibitors

Pan-Raf inhibitors




Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH


1

Ca2+

Ca2+

NO

23

4567

ER

Raf

MEK

ERK

cPLA2

PKD

PKC

SCK

TSAD SRC

PAK

RAC1VAV2

FAK

Paxillin

IQGAP1

YES

SRC

SHB

NCK

FYN

PAK2

CDC42

HSP27

p38 MAPK

p85/PI3K

GAB1

RACPDK1

AKT

BAD

Caspase9

Caspase3/7

Bcl-2

eNOS

IAP

MK

PLCβ3

HSP27

DAG Y801

Y951

VEGFAVEGFCVEGFD

VEGFR2 VE-Cadherin

Y1054Y1059

Y1175Y1175

Y1214

Y1223Y1305Y1309Y1319

Focaladhesionturnover

Membraneruffles,MotilityCell-cell

contacts

SHCASOS

GRB2PGI2

Gene transcription

Actin polymerization,Stress fiber formation

Cross talk with plasmamembrane-associated

heterotrimeric G-protein

Nucleus

Cell Proliferation Cell Migration

Cell Vascular development/Angiogensis

Cell Survival Cell Permeability

PIP2 PIP2

IP3

PIP3

PLC-γ

SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

PAC-1Apoptosis Activator 2

Caspase inhibitorZ-VAD-FMK

Caspase activators

AT-406YM155

IAP inhibitors

DasatinibSaracatinibBosutinibKX2-391

NVP-BHG712

Src inhibitorsPF-00562271

PF-562271NVP-TAE226

PF 573228

FAK inhibitors


Pan-PKC inhibitors


OSU-03012PHT-427

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors

CCT128930(Akt2)


GSK690693GDC-0068


Phospholipase inhibitorVarespladib




Axitinib



MEK

5

S1036 PD0325901

S2673 Trametinib(GSK1120212)

Phase 3

S1102 U0126-EtOH

MEK5

MEK1

MEK1S1177 PD98059

S1020 PD184352 (CI-1040)

Phase 2

Phase 2

Phase 1

S1531 BIX 02189

S2134 AZD8330

Phase 3S7007 MEK162 (ARRY-162, ARRY-438162)

2007

2008

2011

1998

1995

1999

2010

2008

2007

2006

S1008 Selumetinib (AZD6244)

Phase 2

Phase 2

MEK1 Others14 ERK1/2 phosphorylation

OthersMEK5

OthersERK phosphorylation

OthersERK1/2 phosphorylation

OthersMEK-2E

IC50(nM)

MEKIC50(nM) 0.33

MEK1 MEK2IC50(nM) 0.92 1.8

MEK1 MEK270 60IC50(nM)

MEK1IC50(μM) 2

MEK217

MEK117

5~2000

IC50(nM)

IC50(nM)S1475 Pimasertib

(AS-703026)

1.5MEK5

IC50(nM)

MEK1IC50(nM) 7

MEK27

MEK12IC50(nM)


Discov

ery

MEK inhibitors

Licensed by Pfizer

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors


Niclosamide(STAT3)



JNJ 26854165RITA


Pifithrin-α

p53 activators

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors


Pan-PKC inhibitors

IP3 Ca2+

Lin-1

RSK

SOS

ER81

GSK3

BAD IkBα

CREB

ATF4

c-Fosc-Jun

MNK

MNK1

MSK

Histone H3

AKT

ATF1

STAT3

p65

Paxillin

ASK1

TAO1,2

MLK2

MLK3

MLK1 DLKBax

Bid

DUSP1

Bcl2

MEKK1-4

MKK4,7

MEKK1-4

JNK1,2,3

MKK3,6

p38MAPKα,β

p38MAPKα,β

TAK1

Vinexin

MEF2

ATF1/2/6

SAP-1ELK-1

c-Jun

STAT4

JunD

HSF-1

ATF2

ETS-1

NFK3p53

p53

JNK

14-3-3

CREBeEF2K

MK2,3

MAPK

MAP2K

Neurofilament

eIF4E

ERK1,2

PKC Ras

CaMKPLCβ

Cytokines UVInflammatory Stress,LPS

GPCR

MAP3K

LPSCDC40TNFαRII

TCR

TAK1

Pan-Raf inhibitors




Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH


Pan-p38 inhibitors


SB 203580SB 202190

VX-745

BIRB 796(p38α)LY2228820(p38α)


A-Raf

B-Raf

Raf-1

CCT128930(Akt2)


GSK690693GDC-0068


MEK1/2(MM cell lines)



CHIR-98014LY2090314


SB 216763

MEK1,2

ERK1,2

JAK

6

S5001 Tofacitinib Citrate

S2736 TG101348 (SAR302503)

Phase 3

S2162 AZD1480 Phase 1/2

Phase 3

S2789 Tofacitinib Phase 4

S2851 Baricitinib (LY3009104, INCB028050)

Phase 1

Phase 2

Phase 3

Phase 3

S2796 WP1066

S1134 AT9283

S2219 CYT387

2010

2010

2008

2011

2003

2010

2008

2009

2009

2008

2004

S1378 Ruxolitinib (INCB018424)

Phase 2

Phase 4

JAK1 Others3.3

JAK22.8

JAK3428 Tyk2

OthersTyk2

OthersSTAT3/5,ERK1/2

OthersAurora A/B,Abl(T315I)

IC50(nM)

JAK3 JAK2IC50(nM) 1 20

JAK1112

JAK2IC50(nM) 3

JAK11.3

JAK20.26

JAK2 (HEL cells)2.30

JAK21.2

JAK31.1

IC50(nM)

JAK3IC50(nM) 1

JAK220

JAK1112

JAK25.7

JAK3>400

JAK218

JAK39

JAK3155

JAK15.9IC50(nM)

IC50(μM)

IC50(nM)

JAK111

JAK2<3

IC50(nM)

S8004 ZM 39923 HCl JAK37.1

JAK14.4pIC50

IC50(nM)

JAK3

JAK2

JAK3

S2214 AZ 960


Discov

ery

JAK inhibitors

OthersEGFR,TGM2

P

P

PP

P

P

P

P P P

P

P

P

P P

P

PP PP P PP

Tyk2 Tyk2

Antiviral,microbial,tumor responses

STAT2

STAT2

Cell survival LymphopoiesisTh1 differentiation Lymphocyte differentiation

IRF9

IRF9

IRF9

PIAS

PIAS PIASPIAS

PIAS

SHP

SOCS

SHP

SOCS

STAT4

STAT4

STAT4

STAT4

STAT2

STAT2 STAT4 STAT4

IFNγ IFNα/β

IL-10

IL-23

IL-16

IL-12 IL-2 IL-4/IL-13EPO

IL-5 IL-3

GM-CSF


Niclosamide(STAT3)


RuxolitinibAZD1480Cyt387

Pan-JAK inhibitors

TG101348(JAK2)Tofacitinib citrate(JAK3)

Selective JAK inhibitors

JAK2 JAK2JAK1 JAK1JAK2 JAK1 JAK2 JAK2 JAK2 JAK2 JAK1 JAK3 JAK1 JAK3

STAT1 STAT1PP

STAT1P

STAT3P

STAT3P

STAT1

STAT1

STAT1 STAT3

STAT3

STAT1P

P

P P

P

P

STAT1

STAT1

STAT1 STAT3

STAT3

STAT5a

STAT5b

STAT6

STAT6

STAT6

STAT6

STAT5a

STAT5b

STAT5a STAT5bP

STAT5a STAT5bP P P

STAT5a STAT5bPP

STAT6 STAT6PP

P

P P

P P

P

P

P

P

P

P

P

P

Licensed by Pfizer

Licensed by Pfizer

Akt

7

S1113 GSK690693

S1037 Perifosine(KRX-0401)

Phase 3

Phase 2

Phase 1/2

S2808 GDC-0068

S1117 Triciribine

S2635 CCT128930

Phase 1/2

S1558 AT7867

S8019 AZD5363

Phase 4S3056 Miltefosine

2009

2008

2002

2011

1993

2011

2005

2010

2012

1991

S1078 MK-2206 2HCl Phase 2

Phase 1

Akt18

Akt212

Akt365

Akt213

Akt39

OthersPKA,p70S6K

OthersPKA,PKCδ,CDK2,ERK2,GSK-3β

Othersp70S6K,PKA

Othersp70S6K/PKA, ROCK1/2

OthersPKA,PrkX,PKC

OthersHIV-1

IC50(nM)

Akt1IC50(nM) 2

AktIC50(μM) 4.7

Akt1 Akt25 18

Akt38

Akt217

Akt347

Akt38

IC50(nM)

AktIC50(nM) 130

Akt26IC50(nM)

S2670 A-674563

32Akt1

IC50(nM)

11Akt1

Ki(nM)

Akt1IC50(nM) 3

Akt28


overy

Akt inhibitors

Growth factor

RTK

mTORC2

mTORC1

Cell-cycleproliferation

Cell survival

Transcriptiontranslationcell cycle

Cap-dependenttranslation

Proteinsynthesis

IRS

Ras

PIP2 PIP3

PTEN

TSC1 TSC2

Cyclin D1

FOXO

FASL BIM

BADp27kip1

PRAS40

GβL

Raptor Mlst8

4E-BP1 p34cdc2 cyclin E

S6p27kip

pRb

elF4E

elF4A elF4G

elF3

RictorGβLmSIN1

PROTOR/PRR5


OSU-03012PHT-427

CCT128930(Akt2)


GSK690693GDC-0068




CHIR-98014LY2090314


SB 216763

Pan-CDK inhibitorsPD 0332991(CDK4 & CDK6)

Dinaciclib(CDK1,2,5 &9)AT7519(CDK1,2,3,4,5 & 6)Selective CDK inhibitor

BS-181(CDK7)

S6 Kinase inhibitorsBI-D1870

H 89PF-4708671

FMKAT7867

AktmTOR

mTOR

PI3K p100PI3K p85

p70S6K

CDKs

GSK3

c-Myc

MDM2

p53

PDK1

Akt2

Akt1

Miltefosine inhibits PI3K/Akt activity with ED50 of 17.2 μM and 8.1 μM in carcinoma cell lines A431 and HeLa, first oral drug for Visceral leishmaniasis, effective against both promastigotes and amastigotes.

JNJ 26854165RITA


Pifithrin-α

p53 activators

Nutlin-3NSC-207895

Mdm2 inhibitors

10058-F4c-Myc Inhibitor

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors mTOR inhibitorsEverolimus RapamycinAZD8055

KU-0063794PP242

mTOR inhibitorsEverolimus RapamycinAZD8055

KU-0063794PP242

PARP

8

S1004 Veliparib(ABT-888)

S1098 Rucaparib (AG-014699,PF-01367338)

Phase 2

S2178 AG-14361

S7300 PJ34 HCl

S8038 UPF 1069

Phase 1

Phase 1

S7048 BMN 673

S7029 AZD2461

2008

2007

2007

2004

2004

2009

2009

2013

S1060 Olaparib (AZD2281, Ku-0059436)

Phase 2

Phase 2

PARP15

PARP21IC50(nM)

PARP1 PARP2Ki(nM) 5.2 2.9

PARP1Ki(nM) 1.4

PARP1<5

PARP0.58

AZD2461 is a novel PARP inhibitor with low affinity for Pgp than Olaparib.

Ki(nM)

PARP1EC50(nM) 20

PARP220

PARP18.0

PARP20.3IC50(μM)

IC50(nM)

PARP1

PARP2


Discov

ery

PARP inhibitors

Growth factor

Glucose

NAD

NADH

ATP

ARH3 PARG

AMPKactivation

Nicotinamide

RiboseAMP

ADPRunits

ADPR units

Poly ADP-Ribose TSC2 TSC1

Class IPI3K

Atg4A

Live Cell

PARPCleavage

Normal Function Loss of FunctionCancer

ADP-RiboseUnits

Other DNARepair

Enzyme

ROS

ROS

Atg1-Atg13complex

Viable withNo Mutation

Viable withMutation

Autophagy

DNA Damage

DNA Repair

High DamageLow Damage

ATP / NADDepletion

Necrosis

Apoptosisinitiation event

Caspase-3 activation

Genotoxin

raptor

P ARP

mLST8

Znl ZnⅡ Znlll BRCT WGR H Y E* * *NLS

DBD AD Catalytic domain

Transient recruitment and non-covalent andcovalent modifications

of various proteins

XRCC1

Histone H1

MRE11

Other unknown targets

Recruitment of XRCC1 and DNA ligase III to SSBs and repair by BER

Altered chromatin binding during DNA damage and transcription

DSB repair by NHEJ

DSB repair by HR and checkpoint activation

HR and restarting of collapsed replication forks

Genomic maintenance

ADP

CCT128930(Akt2)


GSK690693GDC-0068


Iniparib(PARP1)UPF 1069(PARP2)

Pan-PARP inhibitorsOlaparibABT-888A-966492

Selective PARP inhibitorsRucaparib(PARP1)

PP-121

DNA-PK inhibitorsNU7441PI-103

NU7026PIK-75

Etoposide(Topoisomerase II)Epirubicin(Topoisomerase II)

Selective Topoisomerase inhibitorsTopotecan(Topoisomerase I)

Camptothecin(Topoisomerase I)Irinotecan(Topoisomerase I)

Doxorubicin(Topoisomerase II)BEZ235

Wortmannin

ATM/ATR inhibitorsKU-55933KU-60019VE-821

CP-466722

AMPK activatorsA-769662

AcadesinePhenformin HCl

PARP

PARP

Modulate PARPActivity

Modulate PARPActivity

PARP

AMPK

PI3K

Akt

mTOR

Apoptosis

DNA-PKcs

ATM

Topoisomerase I


KU-0063794PP242

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

mTOR

9

S1039 Rapamycin

S1555 AZD8055 Phase 1

Phase 2

Phase 1

Phase 2

S1226 KU-0063794

S2218 PP242

S1009 BEZ235 (NVP-BEZ235)

S1044 Temsirolimus (CCI-779, NSC 683864)

S1038 PI-103

Phase 1S8040 GDC-0349

1998

2007

2010

2009

2008

2008

2009

2008

2006

2013

S1120 Everolimus (RAD001)

Phase 3

Phase 4

Everolimus is an mTOR inhibitor of FKBP12 with IC50 of 1.6-2.4 nM.

Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM.

AZD8055 is a novel ATP-competitive mTOR inhibitor with IC50 of 0.8 nM with excellent selectivity (~1,000-fold) against PI3K isoforms and ATM/DNA-PK.

KU-0063794 is a potent and highly specific dual-mTOR inhibitor of mTORC1 and mTORC2 with IC50 of ~10 nM; no effect on PI3Ks.

PP242 is a selective mTOR inhibitor with IC50 of 8 nM; targets both mTOR complexes with >10- and 100-fold selectivity for mTOR than PI3Kδ or PI3Kα/β/γ, respectively.

BEZ235 is a dual ATP-competitive PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM/5 nM/7 nM/75 nM/6 nM, respectively. It inhibits ATR with IC50 of 21 nM.

S2811 INK 128 (MLN0128)

Temsirolimus is a specific mTOR inhibitor with IC50 of 1.76 μM.

INK 128 is a potent and selective mTOR inhibitor with IC50 of 1 nM; >200-fold less potent to class I PI3K isoforms, superior in blocking mTORC1/2 and sensitive to pro-invasion genes (vs Rapamycin).

PI-103 is a multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM, less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM.

Cat.No. Product Name Information Clinical TrialDisc

overy

mTOR inhibitors

GDC-0349 is a potent and selective ATP-competitive inhibitor of mTOR with Ki of 3.8 nM, 790-fold inhibitory effect against PI3Kα and other 266 kinases.

P PP

P

P

P P

P P P P P

P

P

PP

P P

P

P PP

Dishevelled

SLC

7A5

GLU

T4

SLC

3A2

Aminoacids

Aminoacids

Ras

LKB1

40S

4E-BP1

4E-BP1

mRNAtranslation

elF4GRHEB

YY1

RHEBSREBP

Lipidsynthesis

Mitochondriaproliferationand function

Metabolism,stress response,apoptosis

Lipidsynthesis SREBP

PCG1α

Energy

PTENSGK

p14

GTP

GDP

GDP

GTP

GTP

GDPp14

MP1

MP1

p18

p18

IRS1

TSC1

ATG101

ATG13

FIP200

RAGA/B

LysosomeRAGC/D

RAGA/BRAGC/D

Gene expression

ULK1

FOXO1,3

FOXO1,3

SESN1,2

DNA damage

Autophagy

REDD1

Hypoxia

TSC2

FrizzledInsulin

receptorInsulin or IGF

Growth factors

Glucose

Glycolysis

Mitochondrion

Secretoryvesicle

Ptdlns(4,5)P2 Ptdlns(3,4,5)P3

elF4BelF3

SKAR

elF4A

S6

PPAR agonistsRosiglitazone

GW501516Ciprofibrate

PPAR antagonistGW9662

CCT128930(Akt2)


GSK690693GDC-0068



H 89PF-4708671

FMKAT7867



Pan-Raf inhibitors




Wnt/beta-catenin inhibitors

IWP-2

XAV-939ICG-001

IWR-1-endo

Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH

AZD6244(MEK1)BIX 02189(MEK5

ERK InhibitorSCH772984

p53 activatorsJNJ 26854165

RITATenovin-1

p53 inhibitorPifithrin-α


OSU-03012PHT-427

mTORC1

mTORC1

mTORC2

P

Raf MEK

PDK1

AMPK

S6K1

p53

ERK

PI3K

GSK3β

Wnt

P

PAktP P

PPARγ

Licensed by Pfizer


KU-0063794PP242


KU-0063794PP242

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors



CHIR-98014LY2090314


SB 216763

CDK

10

S2768 Dinaciclib(SCH727965)

S1153 Roscovitine (Seliciclib,CYC202)

Phase 2

Phase 2

Phase 1

S2679 Flavopiridol HCl

S2621 AZD5438

S7114 NU6027

Phase 2S7158 LY2835219

2004

2010

1997

2002

2009

2000

2011

S1116 PD0332991 HCl Phase 2

Phase 3

CDK4/cyclin D111

CDK6/cyclin D216IC50(nM)

CDK2 CDK5IC50(nM) 1 1

CDK1 CDK93 4

CDK1 CDK2~41 ~41

CDK4 CDK6~41 ~41

Cdc2/cyclin BIC50(μM) 0.65

CDK2/cyclin A0.7

CDK2/cyclin E0.7

CDK5/p350.16

CDK2/cyclin E6

CDK9/cyclin T20

CDK6/cyclin D321

CDK42

CDK610

IC50(nM)

CDK1/cyclin B1IC50(nM) 16

CDK21.3

CDK12.5Ki(μM)

IC50(nM)

OthersCDK7

ATR,DNA-PK

OthersCDK5,GSK-3β

Others


overy

CDK inhibitors

P

P

P

P


Dinaciclib(CDK1,2,5 &9)AT7519(CDK1,2,3,4,5 & 6Selective CDK inhibitor

BS-181(CDK7)

ATM/ATR inhibitorsKU-55933KU-60019

VE-821CP-466722

BEZ235Wortmannin



BS-181(CDK7)

Pan-TGF-beta/Smad inhibitorsLDN193189(ALK2 & ALK3)LY2109761(TβRI & TβRII)SB-505124(ALK4 & ALK5)

Selective TGF-beta/Smad inhibitorsSB 431542(TβRI/ALK5)LY2157299(TβRI/ALK5) SB 525334(TβRI/ALK5)


RITATenovin-1


PLK inhibitorsBI 2536BI6727

RigosertibGSK461364

HMN-214MLN0905

Pan-Chk inhibitorsAZD7762 PF 477736


SCH 900776(Chk1)

Pan-Aurora inhibitorsVX-680

DanusertibZM-447439

Selective Aurora inhibitorsMLN8237(Aurora A)

Barasertib(Aurora B)

Growth Factor Receptor Activation

DNADamage

FoxO1/3

p27 Kip1p21 Cip1

Cyclin-A

Cyclin-A

Cyclin-HE2FRb

Rb

CDC25Ap21

Myc cdc25A

Growth Factor Withdrawal

RbFoxO1 BimFasLTRAIL

Apoptosis

E2F/DP Target Genes:Cyclin E/A, E2F-1/2/3, cdc2, c-Myc, p107, RanGAP, TK, DHFR, PCNA, H2A, etc.

S - P H A S E

M - P H A S E G 2 - P H A S E

DBE

AblE2F

Rb Suv39H1

E2F

OFF ON

14-3-3GADD45p21Cip1

Nuclear Exclusion

BRCA1

cdc25

MDM4 Nuclear Export,Ubiquitination

HIPK2

DNA Repair

Rad52

Rad51

FANCD2

Bora

Cyclin Bcdc2

Cyclin D

DP-1 DP-1

Critically ShortTelomeres

UV IR

G1- PHASE

TRF2 POT1

Cyclin E

p27 Kip1

CDK4/6

CDK7

CDK2

CDK7

CDK2

CDK2

P P

PP

GSK-3β

TGF-β

Smad3Smad4

Akt

ATM/ATR

p53

Chk1/2

HDAC

PLK1

Wee1

Chk1

c-Abl

AurATopoII

MDM2

p53

p53Chk2

DNA-PKATM/ATR

CCT128930(Akt2)


GSK690693GDC-0068


AZD7762PF 477736


SCH 900776(Chk1)

Pan-Chk inhibitors

Wee1Raf1

BEZ235Wortmannin


CP-466722Bafetinib Dasatinib

Bcr-Abl inhibitorsPonatinib

Imatinib MesylateNilotinibWP1130

Wee1 inhibitorMK-1775

PP-121

DNA-PK inhibitorsNU7441PI-103

NU7026PIK-75

Nutlin-3NSC-207895

Mdm2 inhibitors


Selective Topoisomerase inhibitorsTopotecan(Topoisomerase I)

Camptothecin(Topoisomerase I)Irinotecan(Topoisomerase I)

Doxorubicin(Topoisomerase II)

Pan-Raf inhibitorsVemurafenib

SorafenibPLX-4720

Selective Raf inhibitorsGDC-0879(B-Raf)GW5074(C-Raf)

Myc




Pan-HDAC inhibitors



CHIR-98014LY2090314


SB 216763


BTK

11

S7022 GDC-0834

2010

2011

S2680 PCI-32765 (Ibrutinib)

Phase 3PCI-32765 is a potent and highly selective BTK inhibitor with IC50 of 0.5 nM, modestly potent to Bmx, CSK, FGR, BRK, HCK.

GDC-0834 is a novel potent and selective BTK inhibitor with IC50 of 5.9 nM.

Cat.No. Product Name Information Clinical Trial

Discov

ery

BTK inhibitors

PP

PP

P

P

P P

P P

PP

BCR

Lyn/FynLyn/Fyn

Antigen

ERKNFAT

CXCL13/CXCR5interaction Immune

complexFCγRIII

IgαIgβ

α γ2

Lyn/Fyn

PIP2

BLNKPLCγ2

DAG

PKC Ca2+

IP3

PIP3

R406Piceatannol

R788

Syk inhibitors

R406Piceatannol

R788

Syk inhibitors

PCI-32765GDC-0834

BTK inhibitors

SYK SYKSYK

p38

NF-κBJNK

BTK

PI3K


BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

SP600125JNK-IN-8

JNK inhibitorsNF-κB inhibitorsQNZ

Aminosalicylate Sodium

Pan-p38 inhibitors


SB 203580SB 202190

VX-745

BIRB 796(p38α)LY2228820(p38α)

c-Met

12

GAB1

HGF

α-chainc-Met

β-chain

Y1234Y1235

Y1349Y1356

PLCγ SHP2

SHC

GRB2

SOSRAS

N-WASPArp2/3Cadherins

pRBCdk6p27

uPAMMPsFibronectin

PaxillinFAKIntegrins

BadCaspase-9

Cell junctionMigrationInvasion

SurvivalCell polarityActin cytoskeletonMotility

ProliferationCell-cycle progression

Ets1 AP1

Cdc42

CCT128930(Akt2)


GSK690693GDC-0068

Selective Akt inhibitorsA-674563(Akt1)Pan-Raf inhibitors




Niclosamide(STAT3)


SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

CrizotinibForetinib

PHA-665752SU11274

PF-04217903XL-184

c-Met inhibitors


NVP-BHG712

Src inhibitors

SCH772984ERK InhibitorRac inhibitor

NSC 23766

PAK inhibitorIPA-3

RafRac1

PAK

AktERK MAPK

PI3K

STAT3/5

c-SRC

S1111 Foretinib (GSK1363089)

S1070 PHA-665752

S1561 BMS-777607 Phase 1/2

Phase 2

S2753 Tivantinib (ARQ 197)

Phase 3

S1119 Cabozantinib (XL184, BMS-907351)

Phase 1

Phase 1

Phase 1

S2788 INCB28060

S1112 SGX-523

S1114 JNJ-38877605

2007

2009

2003

2009

2010

2011

2011

2009

2008

2003

2009

S1068 Crizotinib Phase 1/2

Phase 2

c-Met 11

ALK24

OthersFlt-1/3/4,Tie2,AXL

OthersTrkA/B,Ron

IC50(nM)

Met KDRIC50(nM) 0.4 0.9

OthersRon,Flt-1/3/4,Kit,PDGFRα/β,Tie-2

OthersRTKs,STKs

OthersLck,VEGFR-2, TrkA/B

OthersRon

c-MetIC50(nM) 9

Axl1.1

Ron1.8

Tyro34.3

c-Met3.9

c-Met0.13

Met4

IC50(nM)

c-MetKi(μM) 0.355

VEGFR20.035

Ret4

IGF-1R1.8

IR1.7

Kit4.6

c-Met1.3IC50(nM)

IC50(nM)

IC50(nM)

c-Met4

Met10

IC50(nM)

S1094 PF-04217903

2009

c-Met4.8IC50(nM)

IC50(nM)S1080 SU11274


Discov

ery

c-Met inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Phase 2

Phase 1/2

Phase 1/2

S1124 BMS-754807

S1361 MGCD-265

Met5.6IC50(nM)

c-Met1

c-Met14

IC50(nM)

IC50(nM)S2859 Golvatinib

(E7050)

Targets

Targets

Targets

Targets Phase 1

Licensed by Pfizer

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

2012

2010

VEGFR1/2/33/3/4

VEGFR216

OthersRon,Tie2

EGFR

13

S1025 Gefitinib (ZD1839)

S1011 Afatinib(BIBW2992)

S2111 Lapatinib Phase 3

Phase 2

S1173 WZ4002

S1028 LapatinibDitosylate

Phase 2

Phase 2

S2150 Neratinib (HKI-272)

S2727 Dacomitinib

S1143 AG-490

1997

2005

2008

2001

2009

2001

2004

2007

1991

1989

1998

S1023 Erlotinib HCl (OSI-744)

Phase 2

Phase 3

Phase 3

EGFR 2IC50(nM)

Tyr1173 (NR6wtEGFR cells)

IC50(nM) 37Tyr992 (NR6wtEGFR cells)

37Tyr1173 (NR6W cells)

26Tyr1173 (NR6W cells)

57

EGFRwt

IC50(nM) 0.5EGFRL858R

0.4EGFRL858R/T790M

10HER214

ErbB29.2

EGFR10.8

EGFR92

HER259

EGFR6

ErbB245.7

ErbB473.7

ErbB213.5

JAK2~10

IC50(nM)

EGFRL858R

IC50(nM) 2EGFRL858R/T790M

8

ErbB29.2

EGFR10.8IC50(nM)

IC50(nM)

IC50(nM)

EGFR0.1

EGFR35

IC50(μM)

S7039 PD168393 EGFR0.7IC50(nM)

IC50(μM)S8009 AG-18


overy

EGFR inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

PPPPP

PPPPP

PLC-γ

ErbB-4ErbB-4 ErbB-4

HER2

PIP3IP3

GAB1GRB2 GRB2

SOS

Ras

Elk

Shc Nck

PAK

JNKK

Crk

CblVav

CaMK

Ca2+

DG

ElkJun

p27p21

Cell cycleprogression

Metabolism

Cell survival

Protein synthesis

Bad

eIF-4EBP

NRG3NRG2

NRG1NRG2

HB-EGFBTCERP Epiregulin

TGFαEGF ARβ-Cellulin Amphiregulin

HER2 HER2 EGFR EGFRErbB-3

ErbB-3 ErbB-3

HER2

No signaling

Cellular targets

AdhesionMigration

Receptorubiquitylation

DegradationA

ctivation byE

rbB2 overexpression

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

CCT128930(Akt2)


GSK690693GDC-0068


Bafetinib Dasatinib



FAK inhibitorsPF-00562271

PF-562271NVP-TAE226

PF 573228


NVP-BHG712

Src inhibitors


Niclosamide(STAT3)


SP600125JNK-IN-8

JNK inhibitors


Pan-PKC inhibitors


NSC 23766Rac inhibitor


Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH


Pan-ErbB inhibitors

Selective ErbB inhibitors

AfatinibAG-490

Lapatinib

Erlotinib(ErbB1/EGFR)Gefitinib(ErbB1/EGFR)

CP-724714(HER2/ErbB2)


SorafenibPLX-4720


PI3K

Akt

STAT5

RafMEK

GSK-3

mTOR p70S6K

ERK

MycSTAT5

PKC

JNK

RacAbl

Src

FAK

EGFR

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


H 89PF-4708671

FMKAT7867


KU-0063794PP242Tideglusib(GSK-3β)

TWS119(GSK-3β)


CHIR-98014LY2090314


SB 216763

Bcl-2

14

S1001 ABT-263 (Navitoclax)

S1057 Obatoclax Mesylate(GX15-070)

S1121 TW-37

S2812 AT101 Phase 2

S1071 HA14-1

S7034 BM-1074

S8061 Sabutoclax

S7200 Apogossypolone(ApoG2)

2006

2008

2007

2007

2006

2000

2013

2010

2008

2013

2012

S1002 ABT-737 Phase 2

Phase 2

Phase 3

Bcl-2 30.3

Bcl-xL78.7

Bcl-w197.8EC50(nM)

Bcl-2 Bcl-xLKi(nM) ≤1 ≤ 0.5

Bcl-w≤ 1

Bcl-xL0.48

Bcl-xL<1

Bcl-xL0.31

Mcl-10.20

Bcl-xL660

Mcl-125

Bfl-10.62

Mcl-10.18

Bcl-2Ki(μM) 0.22

Bcl-xL1.11

Mcl-10.26

Bcl-20.29

Bcl-2<1

Bcl-20.32

Ki(μM)

Bcl-2Ki(μM) 0.32

Bcl-2~9IC50(μM)

Ki(nM)

IC50(μM)

Bcl-235

Bcl-2<0.01

Ki(nM)

S7105 BAM7 Bax3.3EC50(μM)

Ki(nM)S8048 ABT-199

(GDC-0199)


Discov

ery

Bcl-2 inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Growth factor

Stress,UV,Viruses

FasL

Inactive BH3-only

ActiveBH3-only

BADBIM/BOD,BMF,BIDNOXA,HRK/DP5PUMA/BBC3BIK/BLK/NBKMULE

Smac/DiabloApoptosis

Pro-caspase9

Apaf-1

Bcl-w

A1

Bax

DRP1

Bak

Bok

B21

CytochromeC

Mcl1


RITATenovin-1


Caspase activatorsPAC-1

Apoptosis Activator 2Caspase inhibitor

Z-VAD-FMK

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors


Niclosamide(STAT3)


BEZ235Wortmannin


CP-466722


NF-κB inhibitorsQNZ


DNA Damage ATM

STATBcl-2

Bcl-xL

p53

JNK

Pro-caspase3

Caspase9

Caspase3

cIAP

NF-κB

Caspase8

Caspase10

BirinapantAT406

GDC-0152

IAP antagonists

TGF-beta/Smad

15

S2618 LDN-193189

S2704 LY2109761

S2230 LY2157299 Phase 2

Phase 3

S1476 SB525334

S2186 SB505124

S2750 GW788388

S2805 LY364947

S7223 RepSox

2002

2008

2008

2006

2005

2004

2006

2006

2004

2002

S1067 SB431542 TGFβRI/ALK594IC50(nM)

ALK2IC50(nM) 5

ALK330

TGFβRI/ALK5Ki(nM) 38

TGFβRII300

TGFβRI/ALK556

TGFβRI/ALK518

TGFβRI/ALK559

TGFβR-II400

OthersMLK-7K, RIPK2, CK1δ

TGFβRI/ALK5 auto-P4

IC50(nM)

TGFβRI/ALK5IC50(nM) 14.3

ALK4129

TGFβRI/ALK547IC50(nM)

IC50(nM)

IC50(nM)

TGFβRI/ALK5 binding23IC50(nM)

S2907 Pirfenidone


Discov

ery

TGF-beta/Smad inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Pirfenidone is an inhibitor for TGF-β production and TGF-β stimulated collagen production, reduces production of TNF-α and IL-1β, and also has anti-fibrotic and anti-inflammatory properties.

Angiogensis, extracellular matrix,neurogenesis,immunosuppression,

apoptosis induction.

G1 arrestCell Cycle

Gonadal growth,embryo differentiation,placenta formation,etc.

Osteoblast differentiation,neurogenesis,

ventral mesoderm specification.

DNA

DNA

DNADNA

Transcription factors,co-activators,

and co-repressors

TAK1,MEKK1DAXX/JNK

MAPK signalingpathway

Ubiquitin mediatedproteolysis

DNADNA

Left-right axis geterminationMesoderm and endodem.

BM

PRⅠ

BM

PRⅡ

ALK

-1

ActivinR

Ⅰ

ActivinR

Ⅱ

NodalR

Ⅰ

NodalR

Ⅱ

Smad1/5/8

Smad8

Smad6/7

Smurf1/2

Smad2/3Smad2/3

Smad7

Smad2/3 PP2A

Smad6/7

Smad2/3

Pitx2

RhoA

Smad2/3

Smad2/3

SP1p300

DP1E2F4/5

p107

p15

Skp1

Rbx1Cul1

SARA

Smad1/5/8

IdApoptosis

Nodal ActivinA,B,C TGFβ1,2,3 TGFβ BMP2,4





ThiazovivinGSK429286A

Selective ROCK inhibitorsY-27632(ROCK1)Fasudil(ROCK2)

Pan-ROCK inhibitors


H 89PF-4708671

FMKAT7867

Smad1Smad5

Smad2

Smad3

Smad6

Smad4

p70S6K

ROCK1Smad4 Smad4

Smad4

TGFβRⅠ

TGFβRⅡ

TGFβRⅡ

ERK

c-Myc



Proteasome

16

S1013 Bortezomib (PS-341)

S2853 Carfilzomib(PR-171)

S2181 MLN9708

S2180 MLN2238 Phase 3

Phase 1/2

Phase 1/2

Phase 1/2

S1157 CEP-18770 (Delanzomib)

S7049 Oprozomib (ONX 0912)

S4919 Aclacinomycin A

S7027 Lactacystin

1996

1999

2007

2010

2010

2008

2009

1996

1995

1981

2007

S2619 MG-132

Phase 3

Phase 3

Phase 3

Proteasome0.1

Calpain1.2IC50(μM)

20S ProteasomeKi(nM) 0.6

20S Proteasome β53.4 (IC50)

20S Proteasome LMP782

20S Proteasome β50.93 (Ki)

ProteasomeIC50(nM) <5

20S Proteasome β53.4 (IC50)

20S Proteasome β50.93 (Ki)

20S Proteasome β536

IC50/Ki(nM)

IC50/Ki(nM)

Proteasome3.8IC50(nM)

IC50(nM)

S7038 Epoxomicin

S1386 Nafamostat Mesylate


Discov

ery

Proteasome inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Aclacinomycin A inhibits chymotrypsin-like activity of eukaryotic 20S proteasome or multicatalytic proteinase complex (MPC), inhibits hydrolysis of the Leu-pNA bond in Z-E(OtBu)AL-pNA and the Leu-AMC bond in Z-LLL-AMC by the 20S proteasome with IC50 of 18 μM and 16 μM, respectively.

Epoxomicin is a selective proteasome inhibitor with anti-inflammatory activity, inhibits primarily the CH-L activity of the 20S proteasome, while T-L and PGPH catalytic activities are also inhibited at 100- and 1000-fold reduced rate.

Lactacystin is a potent and selective inhibitor of the 20S proteasome.

Nafamostat Mesylate is an anticoagulant.

RING-type

AMP+PPi

ADP+Pi

ProteasomeProteasome

Proteasome

Cellular stress

ARF

Stress

ProteasomeProteasome

Proteasome inhibition



CDC25C

CDK–cyclin BCDK–cyclin A

CDK–cyclin D

CDK–cyclin E

CDC25A, CDC25CKIP1

Apoptosis

Apoptosis

G0M

G2

G1S

WAF1

CDC25B

CDK–cyclin A

ATP

ATP

E1S

S

SCUb

O=

SCUb

O=

N HC O=

S

26S Proteasome

RP

DUBs

DUBs

DUBsCUb

Ub Ub

Ub

Ub Ub Ub Ub

UbUb

Ub

UbUb

Ub

Ub UbUb Ub Ub Ub

O=

SCUb

O= HECT-type

Cellular pathways associated with the proteasome

HECT

RING Finger S

NF-κB

Geneexpression

Geneexpression

Pro-survivalpathway

Senescence

P

P

MG-132Bortezomib

CarfilzomibMLN9708MLN2238

Delanzomib


b-AP15WP1130

NSC 632839IU1

PR-619

DUB inhibitors

b-AP15WP1130

NSC 632839IU1

PR-619

DUB inhibitors

JNJ 26854165Nutlin-3

ThalidomideTAME

NSC-207895

E3 ligase inhibitors

MLN4924PYR-41

E1 activating inhibitors

BAY 11-7082E2 conjugating inhibitors

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors



JNJ 26854165RITA


Pifithrin-α

p53 activators



Mdm2 inhibitorsNutlin-3

NSC-207895

MDM2p53

p53p53

IκB

NF-κBIκB

IκB

NF-κB

IκB kinase

E2

E3

E3

E2

Phase 4

Phase 2

Gamma-secretase

17

S1575 RO4929097

S1594 Semagacestat(LY450139)

S2660 MK-0752 Phase 1/2

Phase 3

Phase 1

Phase 1

Phase 2

S2711 YO-01027

S2714 LY411575

S1528 LY2811376

S7168 LY900009

S1262 Avagacestat(BMS-708163)

2001

2009

2012

2010

2010

2004

2011

2013

2010

2013

S2215 DAPT (GSI-IX)

S7169 LY3039478


Discov

ery

Gamma-secretase inhibitors

LY3039478 is a potent Notch inhibitor with IC50 of 0.41 nM.

RO4929097DAPT

YO-01027Semagacestat

MK-0752BMS-708163

γ-secretase inhibitors

RO4929097DAPT

BMS-708163LY281137MK-0752

Aβ inhibitors

P

P

P

Aβ Plaque

Aβ1-40

Aβ25-35

Aβ1-42

Others

Aβ1-13

Nicd

PS1-NTF PS1-CTF

Cell dysfunctionand death

NicdCSL

NicdCSL

STAT3P300Mam

SMAD1

SMAD4 gfap

astrocyte differentiation

idlhes1

E(spl)

heyherp2hey

GFAPHey

Dll1,3,4/Jagged1,2

β-Secretase

Ca2+




Niclosamide(STAT3)


PSMAD1P

STAT3P

SMAD4

DAPT is a novel γ-secretase inhibitor, which inhibits Aβ production with IC50 of 20 nM in HEK 293 cells.

RO4929097 is a γ secretase inhibitor with IC50 of 4 nM, inhibiting cellular processing of Aβ40 and Notch with EC50 of 14 nM and 5 nM, respectively.

Semagacestat is a γ-secretase blocker for Aβ42, Aβ40 and Aβ38 with IC50 of 10.9 nM, 12.1 nM and 12.0 nM, also inhibits Notch signaling with IC50 of 14.1 nM.

MK-0752 is a moderately potent γ-secretase inhibitor, which reduces Aβ40 production with IC50 of 5 nM.

YO-01027 is a dipeptidic γ-secretase inhibitor with IC50 of 2.6 nM and 2.9 nM for APPL and Notch cleavage, respectively.

LY411575 is a potent γ-secretase inhibitor with IC50 of 0.078 nM/0.082 nM (membrane/ cell-based), also inhibits Notch clevage with withIC50 of 0.39 nM.

LY900009 is a potent Notch inhibitor with IC50 of 0.27 nM.

Avagacestat is a potent, selective, orally bioavailable γ-secretase inhibitor of Aβ40 and Aβ42 with IC50 of 0.3 nM and 0.27 nM, demonstrating a 193-fold selectivity against Notch.

LY2811376 is the first orally available non-peptidic β-secretase(BACE1) inhibitor with IC50 of 239 nM-249 nM, that act to decrease Aβ secretion with EC50 of 300 nM, demonstrated to have 10-fold selectivity towards BACE1 over BACE2, and more than 50-fold inhibition over other aspartic proteases including cathepsin D, pepsin, or renin.

Phase 4

Phase 2

γ-Secretase complexPresenilin

Beta Amyloid

BACE inhibitorAZD3839

GSK-3

18

S1590 TWS119

S1075 SB216763

S2745 CHIR-98014

S2823 Tideglusib Phase 2

Phase 2

S2729 SB415286

S7063 LY2090314

S7198 BIO

S7253 AZD2858

2003

2003

2000

2003

2012

2000

2011

2003

2012

2013

S2924 CHIR-99021 (CT99021) HCl

GSK-3β

GSK-3β

GSK-3α10

GSK-3β6.7IC50(nM)

GSK-3βIC50(nM) 30

GSK-3β0.9

GSK3β31

OthersTYK2,JAK3

OthersCDK1/2/5,Erk2

GSK-3IC50(nM) 34.3

GSK-3β (Human)

0.58

GSK-3β~78

GSK-3α (Human)

0.65

GSK-3α1.5

GSK-35

IC50(nM)

GSK-3βIC50(nM) 60

GSK-3α78IC50(nM)

IC50(nM)

IC50(nM)

GSK-368GSK3α6.9

IC50(μM)

Ki(nM)S7145 AZD1080


Discov

ery

GSK-3 inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

PP

UbUbUb UbUbUbUb

Ca2+

CKI

Axin

Axin

GTP

NFATAPI

ProteasomeCSNK1

DSH

Rho

PLC

CAMK2

PP2A

GTP Ras

MK

elF2B

elF2

TCF/LEF

Frizzled

GTPγβα

α

Growth FactorCadherin

Gene expression

CCT128930(Akt2)


GSK690693GDC-0068


Pan-PKC inhibitorsStaurosporineSotrastaurinEnzastaurin


IWP-2

XAV-939ICG-001

IWR-1-endo


IWP-2

XAV-939ICG-001

IWR-1-endo


IWP-2

XAV-939ICG-001

IWR-1-endo

SP600125JNK-IN-8

JNK inhibitors


TAMEAPC inhibitor

GSK3β

β-cat

β-cat

β-catGSK3

Akt

PI3Kβ-cat MAPK

APC

β-catP

Rac

PKCJNK

Wnt

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

APC



CHIR-98014LY2090314


SB 216763



CHIR-98014LY2090314


SB 216763

Androgen Receptor

19

S1190 Bicalutamide

S2840 ARN-509

S1174 MK-2866 (GTx-024)

Phase 3

Phase 4

Phase 3

Phase 3

Phase 4

Phase 1

S1908 Flutamide

S2604 Dehydroepiandrosterone (DHEA)

S2042 Cyproterone Acetate

S1140 Andarine

S7040 AZD3514

2009

2012

2012

2005

1986

2005

2005

2003

2013

S1250 Enzalutamide (MDV3100)


Discov

ery

Androgen receptor chemicals

Enzalutamide is an androgen receptor antagonist with IC50 of 36 nM.

Bicalutamide is an androgen receptor antagonist with IC50 of 0.16 μM.

ARN-509 is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM, useful for prostate cancer treatment.

MK-2866 is a selective androgen receptor modulator (SARM) with Ki of 3.8 nM, and is tissue-selective for anabolic organs.

Flutamide is an antiandrogen drug, with its active metablolite binding at androgen receptor with Ki values of 55 nM, and primarily used to treat prostate cancer.

DHEA is a 19-carbon endogenous natural steroid hormone.

Andarine is a selective non-steroidal androgen receptor agonist with Ki of 4 nM, tissue-selective for anabolic organs.

AZD3514 is a potent and oral androgen receptor downregulator with Ki of 2.2 μM and has ability of reducing AR protein expression.

Cyproterone Acetate is an androgen receptor antagonist with IC50 of 7.1 nM, as well as a weak progesterone receptor agonist with weak pro-gestational and glucocorticoid activity.

Phase 2

Phase 2

P

P

Androgen

Androgen

Androgen

SHBG/SHBGR

AR

PI3KR1

GTPGα

GαQ

GαIInactive

Active

Active

PTEN

PTEN

ARDegradation

Androgen

Androgen

UbUbUb

RhoA

DAGPLC

GβγGTP

Gα GβGγGDP GαGβGγ GDP

GTP

AC

BAD

Apoptosis

PRK1RANBP9

HIPK3

Ras

GrowthFactorsReceptor

SOS GRB2

SHC

Cell Survival &Cell Growth

PCAF CBP p300TIF2

RSK

IGF-1 CREB

Fox01

Cyclin-D1 HBO1

Calreticulin

PRK7

EFCAB6CAV1

TCF/LEFNRIP1

EIK1SP1SRFc-Fosc-JunSUMO

Growth Factors

TR4DAXX

BIX 02189(MEK5)

Pan-MEK inhibitorsPD0325901

GSK1120212U0126-EtOH

Selective MEK inhibitorsAZD6244(MEK1)

MDV3100

Androgen receptor chemicalsOstarine

Megestrol AcetateGaleteroneAndarine

Dehydroepiandrosterone

Adenylate cyclase activatorForskolin

cAMP production inhibitorBupivacaine

HSP70 inducer

HSP90 inhibitors17-AAGAUY922

Ganetespib17-DMAG

Geldanamycin

Elesclomol

Delanzomib

Proteasome inhibitorsBortezomib

MG-132Carfilzomib

MLN9708MLN2238

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitorsNutlin-3NSC-207895

Mdm2 inhibitors

FingolimodS1P antagonist

CCT128930(Akt2)


GSK690693GDC-0068


Pan-Raf inhibitors






Z-VAD-FMK


H 89A-674563

PKA inhibitors




NVP-BHG712

Src inhibitors


IWP-2

XAV-939ICG-001

IWR-1-endo

Caspase3MDM2

26SProteasome

Ctnn-β

NF-κB

HSP90HSP70

HSP40

HSP90HSP70

HSP40

Src

SIP

GPCR

PKC

PKA

cAMP Akt

BCL2

PI3K Raf

MEK

MAPK

SRC1

SMAD3

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

AR

AR

AR

AR

AR

AR

AR

Bcr-Abl

20

S1026 Imatinib Mesylate (STI571)

S1033 Nilotinib (AMN-107)

S1369 Bafetinib (INNO-406)

S2243 WP1130

Phase 2

Phase 2/3

Phase 2

Phase 3

Phase 2

Phase 2

Phase 2

Phase 1

Phase 2S1021 Dasatinib

S1006 Saracatinib (AZD0530)

S1107 Danusertib (PHA-739358)

S1134 AT9283

2009

1995

2007

2005

2007

2005

2008

2006

2009

2009

S1490 Ponatinib (AP24534)

Abl0.37 1.5

PDGFRα1.1

VEGFR2 FGFR12.2

PDGFR0.1

c-Kit0.1

c-Kit (D816V)37

c-Kit (WT)79

IC50(nM)

v-AblIC50(μM) 0.6

c-Src30

FLT36.6

Aurora A/B/C13/79/61

c-RET31

FGFR47

Aurora A48

JAK21.2

JAK31.1

FGFR136

Bcr-AblIC50(nM) <30

Lyn19

Src0.8

Bcr-Abl5.8

v-Abl30

Bcr-Abl25

IC50(nM)

Bcr-AblIC50(μM) 1.8

Abl0.6IC50(nM)

IC50(nM)

IC50(nM)

Abl (T315I)4

Abl14

IC50(nM)

IC50(nM)S2158 KW-2449


Discov

ery

Bcr-Abl inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

S7194 GZD824

2013 Bcr-Abl (T315I)

0.68Bcr-Abl (WT)0.34IC50(nM)

Targets

Targets

P

P

P

P

P

P

P

P

PPBCR

BCR ABL

ABL

TranscriptionProliferationand survival Degradation

Proliferation

Survival

GDPGTP

Cytoskeletalproteins

Protein synthesis

Altered adhesion/motility

Coiled-coil domain

Dimerization

Kinase domain

GRB2SOS GAB2

RAS

hnRNP E2

C/EBPα

PP2A

SET

CBL CRKLCRK

BAD

BAD

14-3-3

4EBP1FOXO3

SKP2

p27

Activation ofdownstream

targets

RAF1

MEK1/2

ERK

MYC

STAT5

JAK2

PI3K

AKT

mTOR

Bcl-xL

Bcl-xLp70S6

P

P

P

P

P

P

CCT128930(Akt2)


GSK690693GDC-0068


Bafetinib Dasatinib




Pan-JAK inhibitors



FludarabineNSC 74859

Niclosamide

STAT inhibitors



Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH


Pan-Raf inhibitors




ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors


H 89PF-4708671

FMKAT7867

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


KU-0063794PP242

ROCK

21

S1573 Fasudil (HA-1077) HCl

S1459 Thiazovivin

S1474 GSK429286A

Phase 4

ROCK1

ROCK2

S7159 RKI-1447

1997

1999

2010

2007

2012

S1049 Y-27632 2HCl ROCK1 140Ki(nM)

ROCK2Ki(μM) 0.33

PKA1.6

PKG1.6

PKC3.3

ROCKIC50(μM) ~0.5

ROCK114

ROCK263

ROCK26.2

IC50(nM)

ROCK1IC50(nM) 14.5


Discov

ery

ROCK inhibitors

Targets

Targets

Targets

Targets

Targets

P

P

P+

+

-

-

-

LIMK1

LIMK2

LIMK2

mDia

Cdc42 MRCK

MBS

PaxillinPPIδ

MLC

Rho

MLCKmyosinⅡ

F-actin

inactive

Cofilin

G-actin

CofilinMLC

Inactive

Tyr-Cas

Cdc42

Crk

DOCK


NVP-BHG712

Src inhibitors


PF-562271NVP-TAE226

PF 573228


PAK inhibitorIPA-3

PAK inhibitorIPA-3

Pan-ROCK inhibitorsThiazovivin

GSK429286ASelective ROCK inhibitors

Y-27632(ROCK1)Fasudil(ROCK2)

ROCK

FAK

Rac

Src

PAK1

PAK4

Selectivity

Aurora Kinase

22

S1048 VX-680 (Tozasertib, MK-0457)

S1147 Barasertib (AZD1152-HQPA)

S1103 ZM 447439

S1100 MLN8054

Phase 2

Phase 2

Phase 1

Phase 2

Phase 2

Phase 1

S1249 JNJ-7706621


S1134 AT9283

S1529 Hesperadin

2011

2004

2007

2003

2007

2005

2006

2009

2003

2010

S1133 Alisertib (MLN8237)

Aurora A1.2

Aurora A

Aurora B

Aurora A

Aurora B18

Aurora C4.6

IC50(nM)

Aurora AKiapp(nM) 0.6

Aurora B79

Aurora C61

Aurora B4

Aurora B<3

TbAUK140

Aurora C1

Aurora BIC50(nM) 0.37

Aurora B130

Aurora B15

Aurora A110

Aurora A13

Aurora A<3

IC50(nM)

Aurora AIC50(nM) 4

Aurora A11IC50(nM)

IC50(nM)

IC50(nM)

Aurora B (human)250

Aurora A5

IC50(nM)

IC50(nM)S2719 AMG-900


Discov

ery

Aurora Kinase inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

S2770 MK-5108 (VX-689)

2010 Aurora A

0.064IC50(nM)Targets

Targets

HEF1

Bora AjubaPP1

GADD45a

PP2A PTTG1

CNEP-A

CDC25C

Mitotic entry

Eg5 MAP215HURP

Bipolar spindle formation

Targeting of mitoticcheckpoint protein

Cul3/KLHL9/KLHL E3 complexCdc48/p97/deubiquitiylating enzyme

Transfer of AuroraB/CPCfrom centroemre to

central spindle/midzone

MKLP1,MgcRacGAP14,Myosin II RLC

RASSF1A/Syntaxin16,Ev15,BARD1β

Centrosome maturationMicrotubule remodeling

Chromosome inducedMicrotubule formation

Correction of error in kinetochore-microtubule attachmentMitotic spindle checkpoint activation

CDC25B

Katanine

CDC14,MKLP2

Intermediate filaments

Central spindle assemblyCleavage furrow ingression

and cytokinesis

Histone H3

TACC

PP1

Ufd1

EB-1

PP2A

Hec1

Ndc80

MCAK

TPX2

MAP215

INCENP

Borealin

CENP-A

TD-60

Cohesin Chromatin remodelingChfr

PAK1



BS-181(CDK7)

AZD7762PF 477736


SCH 900776(Chk1)

Pan-Chk inhibitors


DanusertibZM-447439



PLK inhibitorsBI 2536BI 6727

RigosertibGSK461364

HMN-214MLN0905

γ-secretase inhibitorsDAPT

RO4929097YO-01027

Semagacestat MK-0752

BMS-708163


Survivin inhibitorYM155

Aurora-A

Aurora-A

Aurora-A Aurora-B

Aurora-B

Aurora-B

Plk1

Wee1

Cdk1/cycB

γ-tubulin

γ-tubulin

Plk1

Survivin

Survivin

Survivin

CDK1/cycBChk1

Selectivity

Aurora A Phase 1

DNA/RNA Synthesis

23

NU7441PI-103

PIK-75NU7026

PP-121

DNA-PK inhibitors KU-55933KU-60019

CP-466722VE-821

BEZ235Wortmannin

ATM/ATR inhibitors

Topotecan(Topoisomerase I)Camptothecin(Topoisomerase I)

Doxorubicin(Topoisomerase II)IIrinotecan(Topoisomerase I)


Selective Topoisomerase inhibitors

OlaparibABT-888A-966492

Selective PARP inhibitorsRucaparib(PARP1)

Iniparib(PARP1)UPF 1069(PARP2)

Pan-PARP inhibitors

TLK1/2

H2AX

BRCA1

CDC25

Double-strand breaks Alkylating agents Replication stress

Apoptosis

DNA Repair

Cell-cycle

Chromatinremodelling

JNJ 26854165RITA

p53 inhibitorTenovin-1

Pifithrin-α

p53 activators


Pan-JAK inhibitors



Nutlin-3NSC-207895

Mdm2 inhibitors


RigosertibGSK461364

HMN-214MLN0905


DanusertibZM-447439






BS-181(CDK7)

Bafetinib Dasatinib



AZD7762PF 477736


SCH 900776(Chk1)

Pan-Chk inhibitors

DNA-PK

JAK ATM ATR

ATM

CHK1

c-Abl

p53

CHK2 PARP

CDK Wee1

Topoisomerase

Aurora Kinnase

PLK

MDM2

S1149 Gemcitabine HCl

S1214 Bleomycin Sulfate

S1215 Carboplatin Phase 2/3

Phase 3

Phase 3

Phase 4

Phase 3

Phase 3

Phase 3

S1224 Oxaliplatin

S1491 Fludarabine

S1135 Pemetrexed

S1209 Fluorouracil(5-Fluoracil, 5-FU)

S2684 CX-5461

2003

2002

1997

2008

1998

1999

1997

20

0320

1119

9020

04

S1166 Cisplatin

S1714 Gemcitabine


Discov

ery

DNA/RNA Synthesis inhibitors

Gemcitabine belongs to the group of medicines called antimetabolites.

Cisplatin is an inorganic and water-soluble platinum complex, which is able to inhibit DNA synthesis by forming DNA adducts.

Gemcitabine HCl is a DNA synthesis inhibitor with IC50 of 50 nM, 40 nM, 18 nM and 12 nM in PANC1, MIAPaCa2, BxPC3 and Capan2 cells, respectively.

Bleomycin Sulfate is a glycopeptide antibiotic and an anticancer agent for squamous cell carcinomas (SCC) with IC50 of 4 nM in UT-SCC-19A cells.

Carboplatin is a DNA synthesis inhibitor that binds directly to DNA and interferes with cellular repair mechanisms.

Oxaliplatin inhibits DNA synthesis by forming DNA adducts.

Fludarabine is a STAT1 activation inhibitor and a DNA synthesis inhibitor.

Fluorouracil is an DNA/RNA synthesis inhibitor, which interrupts nucleotide synthesis by inhibiting thymidylate synthase (TS).

CX-5461 is an inhibitor of rRNA synthesis, selectively inhibits Pol I-driven transcription of rRNA with IC50 of 142 nM, has no effect on Pol II, and possesses 250- to 300-fold selectivity for inhibition of rRNA transcription versus DNA replication and protein translation.

Pemetrexed is a novel antifolate and antimetabolite for TS, DHFR and GARFT with Ki of 1.3 nM, 7.2 nM and 65 nM, respectively.

Phase 3S1648 Cytarabine Cytarabine is an antimetabolic agent and DNA synthesis inhibitor with IC50 of 16 nM in wild-type CCRF-CEM cells.

Phase 3

Phase 3

FGFR

24

S2801 AZD4547

S1264 PD173074


S1018 Dovitinib (TKI-258, CHIR-258)

Phase 2

Phase 2

Phase 2/3

Phase 3

Phase 2

Phase 2

Phase 3

Phase 3

Phase 3

S1010 Nintedanib (BIBF 1120)


S2769 Dovitinib (TKI-258) Dilactic Acid

S1470 TSU-68 (SU6668)

2011

2012

1998

2009

2005

2008

2006

2005

2000

2006

S2183 BGJ398(NVP-BGJ398)

FGFR10.9

OthersFGFR4,VEGFR2

OthersFGFR4,VEGFR2

OthersVEGFR2,Src

c-Kit,VEGFR1/2/3,PDGFRα/βOthers

VEGFR1/2/3,PDGFRα/βOthers

c-RET,TrkAOthers

c-Kit,VEGFR1/2/3,PDGFRα/βOthers

FGFR22.5

VEGFR2100-200

FGFR31.8

FGFR21.4

FGFR31IC50(nM)

FGFR1IC50(nM) 0.2

Aurora A/B/C13/79/61

Bcr-Abl25

VEGFR225

FGFR39

Flt31

PDGFRβ0.008

Flk-1/KDR2.1

FGFR1IC50(nM) ~25

Abl0.37

PDGFRα1.1

FGFR39

Flt31

FGFR237

FGFR3108

FGFR12.2

FGFR47

FGFR18

IC50(nM)

FGFR1IC50(nM) 8

FGFR169IC50(nM)

IC50(nM)

IC50(nM)

FGFR11.2

FGFR148

Ki(μM)

IC50(nM)S1084 Brivanib

(BMS-540215)


overy

FGFR inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

S8024 Tyrphostin AG 1296

1994 FGFR (Swiss 3T3 cells)

12.3c-Kit (Swiss 3T3 cells)

1.8IC50(μM)Targets

Targets

P

P

P

P

P

P

P

P P

P

P

P

P

P

P

P

P

Ca2+

IP3

P

P

Ca2+

IP3

P

P

2+

YX

PH C2N C

Y196

Y306

Y349

Y392nPH cPH

Y436783

1253

771Y471

FGFRL1

nSH2 SH3

GAB1

cSH2

PIP2

FGF FGFSEF

GRB2 SOS Ras

MAPKK

MKP1

Target genesNegative feedback. For example, through SPRY,

SEF, MAPKP3 and MKP1 Downstream transcription factors. For example, FOS, JUN and PEA3

MKP3

SEFB

SPRY

SHP2

N

PTB

PLC-γ

Nucleus

BGJ398AZD4547BIBF1120

Selective FGFR inhibitorsPD173074(FGFR1)

Ponatinib(FGFR1)

Pan-FGFR inhibitors

CCT128930(Akt2)


GSK690693GDC-0068



Niclosamide(STAT3)



Pan-Raf inhibitors




PI3K

Akt

PKC

Raf

MAPKSTAT

FGFR

Licensed by Pfizer

PDGFR0.3-0.5

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

HSP (e.g. HSP90)

25

Hsp60

Hsp27

Hsp27

Hsp27

Bax

PTEN

Daxx

Hsp27

Hsp27

Hsp60

ROS

Hsp27

Cyt.c

Apaf-1

Hsp60

CYPD

AIF

HspB5

Bclxs

Hsp27

tBidASK1

ASK1-Akt

PEA-15

Fas, TRAIL

Mitochondria

TRAP1 CYPD

HspB

HspB5

Nucleus

FKHR

Caspases dependentapoptosis

Pro-apoptotic genes

DNSfragmentation

P-HspB5

Pro-caspase3

Hsp60

HspB5

JNJ 26854165RITA


Pifithrin-α

p53 activators



Z-VAD-FMK

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors

HSP70 inducer

HSP90 inhibitors17-AAGAUY922

Ganetespib17-DMAG

Geldanamycin

Elesclomol


CCT128930(Akt2)


GSK690693GDC-0068


Caspase8 p53

PI3K

Akt

Bcl-2

Survivin

Survivin

Caspase3

Caspase9

Hsp90

Hsp90

Hsp90

Hsp90Hsp70

Hsp70

Hsp70

Hsp70

S1141 17-AAG

S1159 Ganetespib (STA-9090)

S1142 17-DMAG HCl Phase 1

Phase 2

Phase 2

Phase 1/2

Phase 2

Phase 2

Phase 3

Phase 2

S2713 Geldanamycin

S1175 BIIB021

S2639 SNX-2112 (PF-04928473)

S2656 PF-04929113 (SNX-5422)

S1498 NVP-BEP800

2011

2003

2009

2006

1999

2009

2008

2009

2010

2009

S1069 AUY922 (NVP-AUY922)

HSP90α13

HSP90β21IC50(nM)

HSP90IC50(nM) 5

HSP90 (OSA 8 cells)IC50(nM) 4

HSP9062

HSP90α30

HSP90β30

HSP90β

HSP70

HSP9041(Kd)

Her-237(IC50)

IC50(nM)

HSP90Kd(μM) 1.2

HSP90 (N-terminal domain)0.78

HSP901.7(Ki)/38(EC50)Ki/EC50(nM)

Ka(nM)

Kd/IC50(nM)

HSP90β58IC50(nM)

S1163 AT13387


Discov

ery

HSP (e.g. HSP90) inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

S1052 Elesclomol (STA-4783)2008 Elesclomol is a novel potent oxidative stress inducer that elicits

pro-apoptotic events in tumor cells.

Hsp90 (A375 cell)18IC50(nM)

Targets

2010 S7150 VER 155008 Hsp70

0.5Grp782.6IC50(μM)

Targets

Selectivity

Phase 3

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

Hedgehog/Smoothened

26

S2151 LDE225 (NVP-LDE225,Erismodegib)

S1146 Cyclopamine

S2157 LY2940680

S2777 PF-5274857

Phase 2

Phase 3

Phase 1/2

S3042 Purmorphamine

S7092 SANT-1

S8075 GANT61

2009

2010

2009

2011

2012

2006

2002

2007

S1082 Vismodegib (GDC-0449)

Hedgehog3

Smoothened (mouse)

1.3Smoothened (human)

2.5

P-gp3000IC50(nM)

IC50(nM)

SmoothenedIC50(nM) 46

Smoothened5.8 (IC50)

Smoothened4.6 (Ki)

Smoothened receptor1.2

1.5

GLI15

IC50/Ki(nM)

BODIPY-cyclopamine binding to SmoothenedIC50(μM)

Kd(nM)

IC50(μM)


Discov

ery

Hedgehog/Smoothened inhibitors

Targets

Targets

Targets

LY2940680 binds to the Smoothened (Smo) receptor and potently inhibits Hedgehog (Hh) signaling.

Targets

Targets

Targets

Targets

Licensed by Pfizer

Hh

Kif7 Kif7

SuFu SuFu

Gli 1/2/3 Gli 1/2/3

Gli 1/2

Gli 3-R

Gli 3-R

Repressor

no transcription oftarget genes

SuFu

Gli 1/2/3

Gli 1/2/3

G-Proteins

Ptch Ptch Ptch PtchSmo Smo

Smo

Smo

FuSuFuCos2

CI155

FuSuFuCos2

CI155

CI155

CI155

Microtubule

Microtubule

CK1CK1

Slimb

CI75

CI75 Dpp DppPtc

Activation

Release ofMicrotubule

Active

Active

β-Arrestin

β-TrCP

Kif3A

Gli 1/2-Act

Gli 1/2-Act

Microtubules

KCTD11

BMP

Cyclin D Cyclin E

Gli1 Patched HIP

Hedgehog Signaling In Drosophila Hedgehog Signaling In Vertebrates

Off-State Off-StateOn-State On-StatePrimaryCilium

Hedgehog

G-Proteins

G-Proteins

PrimaryCilium

PKA inhibitorsH 89

A-674563

Hedgehog/Smoothened inhibitors & chemicals

VismodegibCyclopamine

LDE225LY2940680PF-5274857

Hedgehog/Smoothened inhibitors & chemicals

VismodegibCyclopamine

LDE225LY2940680PF-5274857


IWP-2

XAV-939ICG-001

IWR-1-endo

Delanzomib

Proteasome inhibitorsBortezomib

MG-132Carfilzomib

MLN9708MLN2238Proteasome

PKA

GSK-3β

PKA

GSK-3β

Wnt

Wnt

Hh Hh



CHIR-98014LY2090314


SB 216763

Src

27

S1006 Saracatinib (AZD0530)

S1014 Bosutinib

S2700 KX2-391 Phase 2

Phase 3

Phase 2

Phase 2

Phase 2

S2202 NVP-BHG712

S7060 PP1

S7008 PP2

2005

2008

2001

2009

2010

1996

2003

S1021 Dasatinib Src0.8

Abl0.6

v-Abl30

Abl1

Src (PLC/PRF/5)

13Src (Hep 3B)

26

c-Kit (WT)/c-Kit (D816V)79/37IC50(nM)

c-SrcIC50(nM) 2.7

SrcIC50(nM) 1.2

Src (HuH7)

9

Lck4

Fyn5

GI50(nM)

c-SrcIC50(μM) 2

c-Abl1.667

Fyn6

Bcr-Abl1000

c-Raf0.395

Lck5IC50(nM)

IC50(nM)


Discov

ery

Src inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

FN1

p190RhoGAP

Shc

Ras

RhoA

Grb2/SOS Paxillin p130 CAS

c-Jun

MLCK Myosin

IL-8

PTK

Growth Factors

Integrin

Angiogenesis Proliferation Motility/Migration/InvasionSurvival

CCT128930(Akt2)


GSK690693GDC-0068


Pan-Raf inhibitors





NVP-BHG712

Src inhibitors


PF-562271NVP-TAE226

PF 573228

SP600125JNK-IN-8

JNK inhibitors



BIX 02189(MEK5)




SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors


Niclosamide(STAT3)


Src

FAKPI3K

Akt

JNK

Raf

MEK1/2

IKK

VEGF

STAT3

p38 MAPK

NF-κB

Caspase 9

Licensed by Pfizer

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors




Axitinib


Erk1/2


IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors

p38 MAPK

28

S1574 BIRB 796 (Doramapimod)

S1077 SB202190

S1494 LY2228820

S6005 VX-702

Phase 1/2

Phase 2

Phase 2

Phase 3

Phase 3

S2726 PH-797804

S1527 Vinorelbine

S2928 TAK-715

2000

2002

2000

2008

2004

2009

2001

2005

S1076 SB203580 p38 MAPK0.3-0.5

PKB3-5IC50(μM)

p38α MAPKKd(nM) 0.1

p38α MAPKIC50(nM) 50

p38β MAPK100

p38α MAPK3.7

p38β MAPK17

p38β MAPK102

Anti-mitotic (Hela cells)1.25

26

p38α MAPK7.1

p38β MAPK200

Kd(nM)

p38α MAPKIC50(nM)

IC50(nM)

IC50(nM)


Discov

ery

p38 MAPK inhibitors

Targets

Targets

Targets

p38α MAPKIC50(nM) 7Targets

Targets

Targets

Targets

S1458 VX-745 p38α MAPK10IC50(nM)

Targets

Targets

TRAF2,3,6

STE20Kinase

MKK3,6

PSD95 CyclinD

MKK4

PKD

eEF2K

HSP27

FLIPs

BAF60

ZNHIT1Bmi-1

MEF2A,C,D

ATF1,2,6

USF1

Siah2 HuR

MK2,3

MK2,3

MSK1,2

ATF1

CREB ER81

Tau

Histone

Wip1

SRF

Bax

MEKK4

MyoD

GRK2 PP2A

PP2A

Rho

Cdc42

ASK1

GPCREGFR Growth factors

Caveolin

Environmental stress Inflammatory cytokines

CCT128930(Akt2)


GSK690693GDC-0068


SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

BIX 02189(MEK5)





IWP-2

XAV-939ICG-001

IWR-1-endo




JNJ 26854165RITA


Pifithrin-α

p53 activators


Niclosamide(STAT3)


VarespladibPhospholipase inhibitor


MEK1,2

p38 MAPKγ p38 MAPKδ

STAT1,3

NF-κB

cPLA2

p53

GSK3β

p38 MAPKα,β

p38 MAPKα,β

β-Catenin

ERK1,2

Rac

Akt

Selectivity

p38α MAPK

p38α MAPK

2000 p38β MAPK

220



CHIR-98014LY2090314


SB 216763

PLK

29

S2235 Volasertib (BI 6727)

S2193 GSK461364

S1362 Rigosertib (ON-01910)

Phase 3

Phase 2

Phase 2

Phase 1

S2898 MLN0905

S1485 HMN-214

S7248 Ro3280

2007

2009

2009

2005

2012

2003

2012

S1109 BI 2536 PLK10.83

PLK23.5

PLK25

PLK356

PLK2260

PLK39.0IC50(nM)

PLK1IC50(nM) 0.87

PLK1Ki(nM) 2.2

PLK19

PLK13

IC50(nM)

PLK1IC50(nM) 2

IC50(nM)


Discov

ery

PLK inhibitors

Targets

Targets

Targets

Targets

Targets

HMN-214 is a prodrug of HMN-176, which alters the cellular spatial orientation of PLK1.

Targets

Selectivity

G1 G2

S

M

G11G0

P

P

PP

Cyclin B1

Ser133

P

Cyclin B1

PLK4

EMI1

Securin

Separase

Kinetochore

Microtubule

SA2

PLk5

MKLP2

MKLP1

PRC1ECT2

GDP

GTP

Prophase Metaphase SAC

AnaphaseRhoA

RhoA

ECT2

Self-priming

Kizuna

HsCYK4 HsCYK4

γ-TuRC

Centriole duplication

DNA replication

PCM

CentriolesCohesion of the PCM

G2 phase

Contractile ringassembly

and contraction

Thr14 Tyr15 CDC25

Wee1/MYT1Inactive Active

M phase

Microtubule

NLP

Centrosome maturation

G2/M transition

Mitotic exit and cytokinesisKinetochore functions and sister chromatide cohesion

Cell Differentiation

Synaptic Homeostasis



BS-181(CDK7)

APC inhibitorTAME


DanusertibZM-447439




RigosertibGSK461364

HMN-214MLN0905

CDK1CDK1

PLK3PLK2

PLK1

PLK1

PLK1

APC/C

PLK3

PLK2

PLK1

Aurora A

P P

PLK1

PLK1

PLK1

PLK1

Syk

30

S1533 R406 (free base)

S2206 R788 (Fostamatinib) Disodium

S2625 Fostamatinib (R788)

S3026 Piceatannol

Phase 1

Phase 1

Phase 2

Phase 2

S8032 PRT062607 (P505-15, BIIB057) HCl

2006

2006

2006

2006

1994

2012

S2194 R406 Syk41IC50(nM)

SykIC50(nM) 41

SykIC50(nM) 41

Piceatannol, a natural stilbene, is a selective Syk inhibitor and ~10-fold selectivity versus Lyn.

IC50(nM)


Discov

ery

Syk inhibitors

Targets

Targets

Targets

Syk41

Adenosine A3 receptor81

Syk1

Fgr81

IC50(nM)Targets

Targets

PP

P

P

P

P

P

PP

PP

P

PP

P

P

P

P

P

P

P

P P

P P

P

Ub

Ub

Ub

Ub

Ub

Ub

Grb2

SOS

PLC-γPLC-γ

NF-κBactivation

p50 p65A20

p50 p65

ShcGads

NCK

VAV

Ras

Leukotrienes

MNKMSK

c-Fos

NFAT

Cytokines

Jun

ATF2CREB

GATA

MAPKAPK2,3,5

SFK

CD19

BLNKYY

CD

79B

YY

CD

79A

SFK

CRAC

receptor

IgLIgH

NFATactivation

MAP kinaseactivation

CA

RD

11 o

ff CARD11 on Proteasome

mTORactivation

Bcl10 Malt1

VAV

SLP-76

Gab2

PIP2

DAG

DAG

Cytoskeletonreorganization

Calmodulin/Calcineurin

Degranulation

Antigen

Ca2+

Ca2+

Ca2+

IP3 IP3

Bcl10

TRAF6

TRA

F6

TRA

F6TA

B2

TAB

2

ZnFZnF

TRAF6

TAK1TAK1

Malt1

Lyn

Bcl10

Malt1

CCT128930(Akt2)


GSK690693GDC-0068



BIX 02189(MEK5)






Niclosamide(STAT3)


R406Piceatannol

R788

Syk inhibitors

PCI-32765GDC-0834

BTK inhibitors

Pan-Raf inhibitors




VarespladibPhospholipase inhibitor



IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors


IKK-γ

IKK-β

IκBα

IKK-α

PKCβ

BTK

c-Raf

MEK1/2

Rac

p38JNK

STATERK1/2

cPLA2

Syk

SykSyk

Akt

IKK IκB

NF-κB

PKC

Syk

PI3K

BTKPI3KBEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

SP600125JNK-IN-8

JNK inhibitors

Microtubule Associated

31

S1150 Paclitaxel

S1241 Vincristine

S1165 ABT-751 (E7010)

Phase 1/2

Phase 3

Phase 3

Phase 3

Phase 2

Phase 2

S1364 Epothilone B

S2195 CYT997

S2775 Nocodazole

1992

2003

1985

2007

1995

2009

1975

1994

2000

S1148 Docetaxel


overy

Microtubule associated inhibitors

Docetaxel, an analog of taxol, is an inhibitor of depolymerisation of microtubules through binding to stabilized microtubules.

Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.

Vincristine is an inhibitor of polymerization of microtubules by binding to tubulin with IC50 of 32 μM.

ABT-751 binds to the colchicine site on β-tubulin and inhibits polymerization of microtubules, not a substrate for the MDR transporter and is active against cell lines resistant to vincristine, doxorubicin, and cisplatin.

1995

Epothilone B is a Taxol-like microtubule-stabilizing agent with EC0.01 of 1.8 μM.

CYT997 is a potent microtubule polymerization inhibitor with IC50 of 10-100 nM in cancer cell lines.

Phase 2/3S2209 Vinflunine Tartrate

Vinflunine Tartrate is a new vinca alkaloid uniquely fluorinated with the properties of mitotic-arresting and tubulin-interacting activity.

Phase 2S1248 Vinblastine Vinblastine inhibits microtubule formation and supresses nAChR activity with IC50 of 8.9 μM.

Nocodazole is a rapidly-reversible inhibitor of microtubule polymerization, also inhibits Abl, Abl(E255K) and Abl(T315I) with IC50 of 0.21 μM, 0.53 μM and 0.64 μM, respectively.

Dvl

cdc42

Par6Par3

aPKC

TAOK

MARK2 Spred1

TESK

Par1

MARK Cofilin

PIP3

LIMKLL5β

TPPP

MT Stability

Plus EndProteins

MT Polymerization

MT Catastrophe

+end GrowthPromoting

+/- end GrowthDestabilizing

Delivery toMT Plus Ends

“DynamicMicrotubules”

Minus End

Focal Adhesions

TauRho

mDIA

EB1 mDIA

EB1

Tiam1

TrioRhoRhoGα

mDIA1

CLIP

CLIP

PAK CaMK ICISXMAP215

PTEN PIP3

Actin Filaments

MAP1b

MCAK

MAP1b CRMP2

StathminCLASP

RhoGEFLR

P

MAPKAPK

RTK

Growth Factors

CLIP

Plus EndEB1

CLIPCLASP

Rho

CCT128930(Akt2)


GSK690693GDC-0068



IWP-2

XAV-939ICG-001

IWR-1-endo

Bafetinib Dasatinib







Niclosamide(STAT3)


H 89A-674563

PKA inhibitors



TAMEAPC inhibitor



BS-181(CDK7)


DanusertibZM-447439



Gαq/o


NVP-BHG712

Src inhibitors

ERKPI3K

AktROCK

GSK-3β

Rac1

APC

Srcc-Abl

Rac1

APC

Stat3

PKACDK1

Aurora BERK

Wnt

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

Phase 3S1297 Epothilone A1995 Epothilone A is a Taxol-like microtubule-stabilizing agent with EC0.01 of 2 μM.

S7204 Fosbretabulin (Combretastatin A4 Phosphate (CA4P)) Disodium

Phase 2Fosbretabulin Disodium is the water-soluble prodrug of Combretastatin A4 (CA4), which is a microtubule-targeting agent that binds at β-tubulin with Kd of 0.4 μM, inhibits the polymerization of tubulin with IC50 of 2.4 μM, also disrupts tumor vasculature.



CHIR-98014LY2090314


SB 216763

Topoisomerase

32

S1225 Etoposide

S1231 Topotecan HCl

S1288 Camptothecin

S1198 Irinotecan

Phase 3

Phase 3

Phase 2

Phase 2

Phase 2

Phase 2/3S2217 Irinotecan HCl Trihydrate

2009

1983

1995

1966

1997

1997

S1208 Doxorubicin


Discov

ery

Topoisomerase inhibitors

Doxorubicin is an antibiotic agent that inhibits DNA topoisomerase II and induces DNA damage and apoptosis.

Etoposide is a semisynthetic derivative of podophyllotoxin, which inhibits DNA synthesis via topoisomerase II inhibition activity.

Topotecan HCl is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM, respectively.

Irinotecan is a topoisomerase I inhibitor for LoVo cells and HT-29 cells with IC50 of 15.8 μM and 5.17 μM, respectively.

Camptothecin is a specific inhibitor of DNA topoisomerase I with IC50 of 0.68 μM.

Irinotecan HCl Trihydrate prevents unwinding of DNA by inhibiting topoisomerase I.

b Replication fork convergence

a Transcription

Hemicatenane Catenated duplexes

Topo II, topo IV, topo VI

Negative supercoils

RNA polymerase

Positive supercoils

b Double-strand-break repairDamage, end-resection

Topo III+ RecQ (for example, BLM)

HJ formation, fill in

No chromosome exchange

HJ resolvase (50% outcome) Chromosome exchange

Topo IB, topo II, topo IV,topo V, topo VI, gyrase

Topo III + RecQ(for example,BLM)

a Replication elongationPrecatenanes

Topo II, topo IV, topo VI

Replisome

Topo IB, topo II, topo IV,topo V, topo VI, gyrase

Positive supercoils

Topoisomerase functions during DNA replication

Topoisomerase functions during transcription and DNA repair









Topo IA, topo IB, topo II,topo V, topo VI, (topo IV)

Licensed by Pfizer

IGF-1R

33

TNFα IGF-1

Shc

PIP1B

SOS1,3

CAPTC10

Cbl

IRS2

IRS3

IRS4p85α

p55α

p50α

p85β

p55γ

p110α

p110β

p110γ

Glucose uptake

Cell growthdifferentitation

Protein synthesis

Glucose synthesis

Ras

CDC42

AS160

Gluconeogenesis Foxo1

PTENp90RSK

Cytokines(IL-6,leptin,ect.)

Rec

Insulin

IR A/BTNFR

IRS1


Selective JAK inhibitorsTG101348(JAK2)

Tofacitinib citrate(JAK3

Pan-JAK inhibitors

GSK1838705

IGF-1R inhibitorsLinsitinib

GSK1904529ANVP-ADW742NVP-AEW541BMS-536924

CCT128930(Akt2)


GSK690693GDC-0068

Selective Akt inhibitorsA-674563(Akt1)PDK-1 inhibitors

BX-912BX-795

OSU-03012PHT-427


Niclosamide(STAT3)





JNK

JAK

STAT

PI3K PDK1 PKCζ/γ

GSKα/βAkt1 Akt2 Akt3

ERK1/2

mTOR

IGF-1R

S1034 NVP-AEW541

S1012 BMS-536924

S1093 GSK1904529A

S1124 BMS-754807

Phase 3

Phase 2

S1088 NVP-ADW742

S2703 GSK1838705A

S1234 AG-1024

2009

2004

2005

2009

2009

2004

2009

1997

S1091 OSI-906 (Linsitinib) IGF-1R35

IR75IC50(nM)

IGF-1RIC50(nM) 86

IGF-1RIC50(nM) 100

IR73

IR25

IR2300

IGF-1R1.8

IR1.7

IR2.8

IR1.6

IGF-1R2

0.17

IGF-1R7

IR57

IC50(nM)

IGF-1RIC50(μM)

IC50(nM)

IC50(μM)


Discov

ery

IGF-1R inhibitors

Targets

Targets

Targets

IGF-1RIC50(nM) 27Targets

Targets

Targets

Targets

S8003 PQ 401 IGF-1R<1IC50(μM)

Targets

Targets

2006

OthersMet,TrkA,TrkB

OthersALK

Phase 3

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


KU-0063794PP242



CHIR-98014LY2090314


SB 216763

Rac


PDGFR

34

PLC-γ

PIP2

SRF SRF

SRF SRF

SRFElk-1

Elk-1

Elk-1SRF

SRFElk-1 SRF

EBSSIF

c-Fos c-Jun

AP-1 expressionSIE

SRE

CK ll

CK ll

H2O

DG

IP3

Y720

Y572JMD

K1

KID

K2

C-terminal

JMD

K1

KID

K2

C-terminal

SHP2

p85

SHP2

CRK

Adaptor/Effector Protein

Y579 SHC

SHC

Y581

Y716 GRB2Y740Y751

Y763 SHP2

Y771 SHC

Y775

Y1009Y1021 PLC-γ

Adaptor/Effector Protein

Y731Y742

Y754

Y762

Y988Y1018

p85 NCK

Ras

MEKK-1

c-Jun c-Jun

Ptase

Ptase

TPA

TPA

JNKK

RasGTP

PDGFAA PDGFCC PDGFAB PDGFDD PDGFBB

GTPGDP

GDP Pi

GAP

GRB2

SHP2


Pan-Raf inhibitors




BIX 02189(MEK5)




Sunitinib Malate(PDGFRβ)CP 673451(PDGFRβ)

Pan-PDGFR inhibitorsImatinibPP-121

BIBF1120Selective PDGFR inhibitors

Crenolanib(PDGFRα)


Niclosamide(STAT3)




NVP-BHG712

Src inhibitors

STATs

STATs

STATsSTATs

PKC

SRCSTAT5

STAT5

SRC

Raf-1

MEK

JNK

S2475 Imatinib

S2730 Crenolanib (CP-868596)

S1536 CP-673451

S2622 PP121

Phase 2

Phase 2

Phase 4

Phase 2/3

Phase 2

Phase 2

Phase 3



S1026 Imatinib Mesylate (STI571)


2003

1995

2011

2005

2008

2004

2009

1995

2005

1994

S1042 Sunitinib Malate PDGFRβ 2

Othersv-Abl

Hck,mTOR,Src,AblOthers

B-Raf,VEGFR2Others

VEGFR2,FGFR1,SrcOthers

v-AblOthers

Flt3, c-Kit, FGFR1/3, VEGFR1/2/3Others

c-Kit100

PDGFRβ3.2

VEGFR2 80IC50(nM)

PDGFRIC50(nM) 100

Abl0.37

c-Kit100

PDGFRβ27

PDGFRαKd(nM) 2.1

PDGFRβ1

VEGFR212

Raf-16

PDGFRα10

PDGFRα1.1

PDGFR100

IC50(nM)

PDGFRIC50(nM) 2

PDGFRβ57IC50(nM)

IC50(nM)

IC50(nM)

PDGFRα210

PDGFR0.3-0.5

IC50(nM)

IC50(μM)S8024 Tyrphostin AG 1296


Discov

ery

PDGFR inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Licensed by Pfizer

ERK

ERK


CFTR

35

S1144 Ivacaftor (VX-770)

S1565 VX-809

S6003 Ataluren (PTC124)

Phase 3

Phase 2

Phase 3

Phase 3

2013

2009

2011

2007

S7059 VX-661


Discov

ery

CFTR chemicals

VX-661 is a second F508del CFTR corrector and is believed to help CFTR proteinreach the cell surface.

Ivacaftor is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively.

VX-809 acts to correct CFTR mutations common in cystic fibrosis by increasing mutant CFTR (F508del-CFTR) maturation, with EC50 of 0.1 μM.

Ataluren (PTC124) selectively induces ribosomal read-through of premature but not normal termination codons, with EC50 of 0.1 μM, may provide treatment for genetic disorders caused by nonsense mutations.

NBD2 NBD2

RACK1PDZ1 PDZ2

NHERF1

RhoPIP2

PP2A

Ezrin

Munc-18a

NHERF1

Myosin-VI

NHERF1Myosin-Vb

RA

B11

SY

N1A

SN

AP

23

ERM

N

C C

Ezrin

TC10GTP

CAL

TC10SYN6

SYN6

Lysosomes

CAL

CAL

CAL

CAL

TGN

Earlyendosome

Recyclingendosome

Recyclingendosome

Endocytic pathway

Recycling pathway

Ezrin

NHERF1Ezrin

NHERF1Ezrin




CFTR chemicalsAtalurenVX-809

Ivacaftor

PKA inhibitorsH 89

A-674563

PKA inhibitorsH 89

A-674563

CFTR CFTR

AMPK

PKC

PKA

PKC

PKA

Wnt/beta-catenin

36

S2662 ICG-001

S7085 IWP-2

S7086 IWR-1-endo

S7096 KY02111

S7037 Wnt-C59 (C59)

2009

2004

2009

2009

2012

2012

S1180 XAV-939

Cat.No. Product Name Information

Discov

ery


XAV-939 selectively inhibits Wnt/β-catenin-mediated transcription through tankyrase1/2 inhibition with IC50 of 11 nM/4 nM, regulates axin levels and does not affect CRE, NF-κB or TGF-β.

ICG-001 antagonizes Wnt/β-catenin/TCF-mediated transcription and specifically binds to CBP with IC50 of 3 μM, but is not the related transcriptional coactivator p300.

IWP-2 is an inhibitor of Wnt processing and secretion with IC50 of 27 nM, selective blockage of Porcn-mediated Wnt palmitoylation, does not affect Wnt/β-catenin in general and displays no effect against Wnt-stimulated cellular responses.

Frizzled

ub

ub

Frizzled Frizzled

MKK3/6cGMP

IP3

Cdc42

Cdc42

MKK7

Actin cytoskeletonCell adhesion

DAG

XRNF 185

Daam1

Paxillin

Profilin

RhoA

TK

WIF

Fer

Apc

WTX

p120

MRLC

PIP2

PKG

CaMK

TAK1

NLK

Ca2+

CNA

GMP

Dvl

Naked

PAR-1

DKKs SFRP

CK1α

CYLD

PKCδCK1ε

Axin

PAR-1

LRP

5/6

LRP

5/6

Activated Canonical Wnt Signaling

Activated Non-canonical Inactivated Wnt SignalingsFRP

Ror2

RTKCadherin

G protein DvlG protein

GeneExpression

Tankyrase

PP2A

β-TrCP

ATF2 NFAT ATF2

TCF1

PPARδ

UbC4

COX2

Gastrin

NRSFENC1

c-Jun

NRCAM Cldn1FRA1

MMP7

Cell FateProliferation,Differentiation,Adhesion andSurvivalCell Fate

Proliferation,Differentiation,Adhesion and

Survival

uPAR

CyclinD1

Vimentin

β-TrCPc-Jun

PLC

DvI

AxinCK1ε DvlDvl

Chibby

LEF/TCF

RARICATPYGO

CBP

RABCL9


IWP-2

XAV-939ICG-001

IWR-1-endo


IWP-2

XAV-939ICG-001

IWR-1-endo

Tadalafil(PDE5)Sildenafil citrate(PDE5)

GSK256066(PDE4B)Rolipram(PDE4)

PF-2545920(PDE10A)

Selective PDE inhibitors

BortezomibMG-132


Delanzomib




c-Myc Inhibitor10058-F4





SP600125JNK-IN-8

JNK inhibitors

JNJ 26854165RITA


Pifithrin-α

p53 activators



BS-181(CDK7)


NVP-BHG712

Src inhibitors

GBP

Wnt Wnt Wnt Wnt

p38PKC

PI3KRac1

ROCK

JNK

Proteasome

Survivin

c-Myc

PDE6

p53Cdk8

β-catenin

β-catenin

β-catenin

β-catenin

β-catenin

GSK-3

GSK-3 α-catenin

Src

IWR-1-endo is a Wnt pathway inhibitor with IC50 of 180 nM, induces Axin2 protein levels and promotes β-catenin phosphorylation by stabilizing Axin-scaffolded destruction complexes.

KY02111 promotes differentiation of hPSCs to cardiomyocytes by inhibiting Wnt signaling, may act downstream of APC and GSK3β.

Wnt-C59 is a PORCN inhibitor for Wnt3A-mediated activation of a multimerized TCF-binding site driving luciferase with IC50 of 74 pM.

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

Rac1

SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors



CHIR-98014LY2090314


SB 216763

HER2

37

S2150 Neratinib (HKI-272)

S2192 AZD8931

S2216 Mubritinib (TAK 165)

Phase 3

Phase 2S1167 CP-724714

S1011 Afatinib(BIBW2992)

Phase 2

Phase 1

Phase 3

Phase 1/2

S2111 Lapatinib

S1194 CUDC-101

S1019 Canertinib (CI-1033)

2001

2004

2010

2006

2007

2008

2001

2010

2000

2004

2006

S1028 Lapatinib (GW-572016) Ditosylate

Phase 2

Phase 2

Phase 2

HER2/ErbB29.2

EGFR10.8IC50(nM)

HER2IC50(nM) 59

EGFR92

HER2/ErbB2IC50(nM) 3

EGFR4

ErbB34

HER2/ErbB26

HER2/ErbB29.2

EGFR10.8

HER215.7

EGFR2.4

HDAC4.4

EGFR1.5

EGFR2

IC50(nM)

HER2/ErbB2IC50(nM) 10

EGFRwt

0.5EGFRL858R

0.4EGFR L858R/T790M

10HER214IC50(nM)

IC50(nM)

IC50(nM)

HER2/ErbB29.0

HER2/ErbB26

IC50(nM)

S1056 AC480 (BMS-599626)

HER232

HER122

HER4190IC50(nM)

IC50(nM)S1486 AEE788

(NVP-AEE788)


Discov

ery

HER2 inhibitors

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets Phase 1

PPPPP

PPPPP

PLC-γ

ErbB-4ErbB-4 ErbB-4

PIP3IP3

GAB1GRB2 GRB2

SOS

Ras

Elk

Shc Nck

PAK

JNKK

Crk

CblVav

CaMK

Ca2+

DG

ElkJun

p27p21

Cell cycleprogression

Metabolism

Cell survival

Protein synthesis

Bad

eIF-4EBP

NRG3NRG2

NRG1NRG2

HB-EGFBTCERP Epiregulin

TGFαEGF ARβ-Cellulin Amphiregulin

HER2 HER2 EGFR EGFRErbB-3

ErbB-3 ErbB-3

HER2

No signaling

Cellular targets

AdhesionMigration

Receptorubiquitylation

DegradationA

ctivation byE

rbB2 overexpression

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

PPPPP

CCT128930(Akt2)


GSK690693GDC-0068


Bafetinib Dasatinib




PF-562271NVP-TAE226

PF 573228


NVP-BHG712

Src inhibitors


Pan-GSK3 inhibitorsCHIR-99021CHIR-98014LY2090314

Selective GSK3 inhibitorsSB 216763(GSK-3α)


Niclosamide(STAT3)


SP600125JNK-IN-8

JNK inhibitors


Pan-PKC inhibitors




Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH



SorafenibPLX-4720


PI3K

Akt

STAT5

RafMEK

GSK-3

mTOR p70S6K

ERK

MycSTAT5

PKC

JNK

RacAbl

Src

FAK

EGFR

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


H 89PF-4708671

FMKAT7867


KU-0063794PP242

AZD8931Afatinib

HER2 inhibitorsLapatinib Ditosylate

CP-724714MubritinibNeratinib

HER2

TNF-alpha

38

TNFα TNFα/β

TRADD

FADDTRAF2

MEKK1

MKK7

AP-1

ASK1 RIP

MEKKs NEMO

Apoptosis Inflammation and survivalProteasome IκBdegradation

NIK

TNFR1 TNFR2

SP600125JNK-IN-8

JNK inhibitors




Caspase activators

AT-406YM155

IAP inhibitors



IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors

LenalidomidePomalidomideNecrostatin-1

TNF-alpha inhibitors

Caspase8

Caspase3

cIAPS

JNK

p38 NF-κB

NF-κB

IκB

IKKβIKKαP

P

S1029 Lenalidomide (CC-5013)

S1567 Pomalidomide

S1193 Thalidomide

S4902 QNZ (EVP4593)

Phase 3

Phase 2

Phase 3

2005

1999

1999

1960

2003

S8037 Necrostatin-1


Discov

ery

TNF-alpha inhibitors

Necrostatin-1 is a specific RIP1 inhibitor and inhibits TNF-α-induced necroptosis with EC50 of 490 nM.

Lenalidomide is a TNF-α secretion inhibitor with IC50 of 13 nM.

Pomalidomide inhibits LPS-induced TNF-α release with IC50 of 13 nM.

QNZ shows potent inhibitory activity toward both NF-κB activation and TNF-α production with IC50 of 11 nM and 7 nM, respectively.

Thalidomide was introduced as a sedative drug, immunomodulatory agent and alsois investigated for treating symptoms of many cancers. Thalidomide inhibits an E3 ubiquitin ligase, which is a CRBN-DDB1-Cul4A complex.

ERK

SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

PKC

39

S2791 Sotrastaurin

S1314 Zoledronic Acid

S1055 Enzastaurin (LY317615)

Phase 2

Phase 2

S2911 Go 6983

S8064 Midostaurin (PKC412)

Phase 3S4066 Dequalinium Chloride

S7207 Ro 31-8220 Mesylate

S7208 GF109203X

1986

2009

1996

2005

1996

1996

1993

1993

1991

S1421 Staurosporine Phase 2

Phase 2

Phase 3

α 2

γ5

η4

δ20

ε73

β0.64

α0.95

η1.8

δ2.1

β6

α39

γ83

ε110

IC50(nM)

Ki(nM)θ0.22

βI24

βII14

ε24

γ27

α5

βI17

α20

γ20

βII16

α7

β7

δ10

ζ60

γ6

PKC7-18

IC50(nM)

IC50(nM)

γ24

β30

α22IC50(nM)

IC50(μM)

IC50(nM)

IC50(nM)


Discov

ery

PKC inhibitors

PKC

PKC

A potent nitrogen-containing bisphosphonates. It inhibited proliferation of human foetal osteoblastic cell line (hFOB) with an IC50 of 40 μM.

PKC

PKC

PKC

Targets

PKC

PKC

ζ ζ

cAMP

Gα Gβγ

AC

CREB

Par6-PKCδ

CDC42

DAG

DIg

CPI17

MELC

MLCP

ElkMEF

CM

MDAC

LAT

PLCγ

NFAT

GPCR

LPR6 Fz-1

Growth Factor

c-Fos c-Jun

Ras

SOS

polarization

MHCII

TCR




NVP-BHG712

Src inhibitors


Pan-PKC inhibitors

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors


SorafenibPLX-4720


Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH




Pan-PKC inhibitors





IWP-2

XAV-939ICG-001

IWR-1-endo

ROCK

PKC

PKC

GSK3β

Raf-1IKK

IKB

NF-ĸB

NF-ĸB

ERK

MEK

PKCθRaf

MEK

Wnt

Src

PKC-mu



CHIR-98014LY2090314


SB 216763

Chk

40

T68

T11

T383

T387

S1981

53BP1

BRCA

1

MD

C1

H2A

.X

MRN

ATRIP

Rad17 9-1-1

14-3-3

S317

S345

Noxa

Puma

RFC

Tipin

Timeless

Histone H3

FANCE

Rad51

Cdc25C

Cyclin B Cyclin E/A

Cdc25A Cdc7

Gadd45 Cdc45

BubR1

Mcm2-7

TLS

Chromatinassembly

G2/M G1/S Origin firing Fork restart

Mataphase Anaphase

Stalled fork stabilityIntra-S

SpindleformationChromatid

segregationCytokinesis

etc.

DNA pol α14-3-3σ

PCNA Tlks

p21

Cross-linkrepair

Transcription

Apoptosis

DNA repairHRR

DSB repair

Nuclear export

Ubiquitination

ProteasomaldegradationTr

ansc

riptio

n

TopBP1

BRCA1

Clas

pin

MDC1

Double Strand Breaks/DSBs

Single-Strand Breaks/SSBs

Stalled replication forks

DNA Damage Checkpoints DNA Replication Checkpoint

Spindle Checkpoint

ssDNA

SCFAPC/C

P

P

P P P PUb

ATMATM

p53

Aurora B

APC/CCdc20

Mdm2

Plk1p53

Cdk2

DNA-PK

Caspase-2/3

ATM

Chk2 Chk2

Chk2

Cdk1

Chk1

ATR

RPA

P

P

P

P

PP

P

P

P P


DanusertibZM-447439



APC inhibitorTAME

DNA-PK inhibitorsNU7441PI-103NU702PIK-7

PP-121


RigosertibGSK461364

HMN-214MLN0905

BEZ235Wortmannin


CP-466722

BEZ235Wortmannin


CP-466722


NSC-207895

AZD7762

PF 477736(Chk1)


SCH 900776(Chk1)

Pan-Chk inhibitors



BS-181(CDK7)

JNJ 26854165RITA


Pifithrin-α

p53 activators



Caspase activators

S2735 MK-8776 (SCH 900776)

S2626 LY2603618

S2683 CHIR-124

S2904 PF-477736

Phase 1

Phase 1/2

Phase 2

Phase 1

2008

2011

2010

2007

2008

S1532 AZD7762 Chk15

Chk2<10IC50(nM)

Chk1 Chk1

Chk1

Chk1

Chk1

IC50(nM) 3

Chk247

Chk10.3IC50(nM)

Chk1Ki(nM) 0.49


Discov

ery

Chk inhibitors

Targets

Targets

LY2603618 is a selective Chk1 inhibitor with potential anti-tumor activity.

Targets

Targets

Selectivity

ALK

41

S2762 CH5424802 (Alectinib)

S2703 GSK1838705A

S1068 Crizotinib Phase 1/2

Phase 1/2S7000 AP26113

S7106 AZD3463

Phase 3S7083 LDK378

2007

2011

2009

2007

2011

2004

2013

S1108 TAE684

Phase 2

ALK3

ALKF1174L

1ALKR1275Q

3.5

ALK24

c-Met11

IC50(nM)

IC50(nM)ALK1.9

FER1.3

FLT32.1

IGF-1R8

IR7

ALK0.62

ALK0.2

IC50(nM)

IC50(nM)

ALK0.75Ki(nM)

IC50(nM)


Discov

ery

ALK inhibitors

Targets

Targets

Targets

ALK0.5

IGF-1R2

IR1.6IC50(nM)

Targets

Targets

Targets

Targets

Licensed by Pfizer

P

PP

P

P

Cell Proliferation

DAG

PLC

Jun

AP1

P21

CyclinD

SHP1

ALK

FOXO3a

BIM

p27

Gli

CyclinDBAD

MCL1

CanonicalPathway

TRAF2degradation

AlternativePathway

c/EBPβ

Pleiothrophin

Bcl-xL

SHH

NP

M

WT

NP

MA

LK

165

432

TKdomain

Bcl3

JunB

CD30CD30

AP1

TRAF2

p21

CD

30

152-6418

664567

IRS-1

SHC

GRB2

Ras

Cell Survival

Angiogenesis

Cell cycle progressionProliferation

PLC-γ

MidkineNF-κB inhibitorsQNZ


Pan-MEK inhibitors


PD0325901GSK1120212U0126-EtOH



Pan-JAK inhibitors


Selective JAK inhibitors TAE684CH5424802

GSK1838705A

ALK inhibitors

Crizotinib




H 89PF-4708671

FMKAT7867


Niclosamide(STAT3)


CCT128930(Akt2)


GSK690693GDC-0068


ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors

SP600125JNK-IN-8

JNK inhibitors



NVP-BHG712

Src inhibitors

PKC

JNK

PI3K

AKT

mTORGSK-3 p70S6K

Survivin STAT3

Bcl-2

STAT5ANF-κB

STAT3

STAT3

STAT3

NF-κB

STAT5B

JAK3

JAK2SRC

MEK

P

P

STAT3

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


KU-0063794PP242

ERK1/2

ERK1/2

ALK



CHIR-98014LY2090314


SB 216763

ATM/ATR

42

BEZ235Wortmannin


CP-466722


NSC-207895



BS-181(CDK7)

JNJ 26854165RITA


Pifithrin-α

p53 activators

DNA double strand breaksDNA double strand breaks,

Replication stress, UV

cdc25A

G1 S G2 M

cdc25Ccdc25C

p21

Dbf4

14-3-3

Cyclin E Cyclin E

Cyclin B Cyclin B

P

P P

P

Ub

P

ATM ATR

Chk2

CDK2 CDK2

p53P

p53MDM2

CDK7

Chk1P

CDK1 CDK1P P

S1570 KU-60019

S2245 CP-466722

S1009 BEZ235 (NVP-BEZ235)

Phase 4

Phase 2

S2758 Wortmannin

S2817 Torin 2

S8007 VE-821

S7136 CGK 733

2004

2009

2008

2008

1992

2011

2011

2006

S1092 KU-55933 ATM12.9 (IC50)

ATM2.2 (Ki)IC50/Ki(nM)

ATMIC50(nM) 6.3

ATR Othersp110α/γ/δ/β,mTOR(p70S6K)

OthersPI3K,DNA-PK

OthersmTOR,DNA-PK

21

ATR13 (Ki)

ATR26 (IC50)

ATM200

ATR200

IC50(nM)

ATMIC50(nM) 150

ATR1800

ATR35

ATM28IC50(nM)

Ki/IC50(nM)

IC50(nM)


Discov

ery

ATM/ATR inhibitors

Targets

Targets

CP-466722 is a potent and reversible ATM inhibitor, does not affect ATR and inhibits PI3K or PIKK family members in cells.

Targets

Targets

Targets

Targets

Targets

AZD7762

PF 477736(Chk1)


SCH 900776(Chk1)

Pan-Chk inhibitors

PDE

43

S1431 Sildenafil Citrate

S2515 Vardenafil HCl Trihydrate

S2687 PF-2545920

Phase 2

Phase 2

Phase 1

S1512 Tadalafil

S1430 Rolipram

Phase 3S1455 Cilomilast

S2620 GSK256066

S4019 Avanafil

2001

1996

2001

2005

2004

1983

1998

2009

2000

S2131 Roflumilast Phase 4

Phase 3

Phase 4

Phase 4

PDE40.2~4.3

PDE10A0.37

IC50(nM)

PDE4B3.2

PDE51

PDE51.8

LPDE4100

HPDE4120

IC50(nM)

IC50(nM)

IC50(nM)

IC50(pM)

IC50(nM)


Discov

ery

PDE inhibitors

Targets

Sildenafil Citrate is an agent used to treat erectile dysfunction and pulmonary arterial hypertension (PAH).

Targets

PDE50.5

PDE1180IC50(nM)

Targets

Targets

Rolipram is a PDE4-inhibitor and an anti-inflammatory agent.

Targets

Targets

Targets

Phase 4

Phase 3

S1294 Cilostazol

S8034 Apremilast (CC-10004)

1999

1998

PDE30.2

PDE474

TNF-α77

IC50(μM)

IC50(nM)

Targets

Targets

G-proteinNO

NO

PKG

cGMP

KinasePhosphatase

Guanylatecyclase

Solubleguanylatecyclase

iNOS/eNOS

iNOS/eNOS

Adenylate cyclase

Adrenergic Receptor Epinephrine

Natriuretic peptides guanylins

mitoKATP channel

PF-2545920(PDE10A)

Selective PDE inhibitorsTadalafil(PDE5)

Sildenafil citrate(PDE5)GSK256066(PDE4B)

Rolipram(PDE4)


Alfuzosin HCl

Adrenergic receptorantagonists & agonists

Doxazosin MesylateSalbutamol SulfateIndacaterol Maleate

Mirabegron

PF-2545920(PDE10A)

Selective PDE inhibitorsTadalafil(PDE5)

Sildenafil citrate(PDE5)GSK256066(PDE4B)

Rolipram(PDE4)

Adenylate cyclase activatorForskolin

cAMP production inhibitorBupivacaine

PKA inhibitorsH 89

A-674563

cAMP

PDE3PDE4

PDE5PKA

ERK

FLT3

44

CBL

SHCSHIP

SHP2 GAB2

GRB2

RAS

ELKRSK

CREB

60S

mRNA5′

3′

Proteins

Translation

TMJM JM

TM

L

K K K K

P P

P

P P

BAD

elF4E

40S

4E-BP1

Transcription

FLT3

CCT128930(Akt2)


GSK690693GDC-0068


QuizartinibDovitinib

TandutinibKW 2449

ENMD-2076

FLT3 inhibitors

Pan-Raf inhibitors





H 89PF-4708671

FMKAT7867

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors


BX-912BX-795

OSU-03012PHT-427

PDK-1 inhibitors


Niclosamide(STAT3)


BIX 02189(MEK5)




PI3K

Raf

MEKp38

STAT

Bcl-2

Akt

PDK-1

mTOR

S6K

S1526 Quizartinib (AC220)

S1043 Tandutinib (MLN518)

S2769 Dovitinib (TKI-258) Dilactic Acid

Phase 2

Phase 3

Phase 1S2158 KW-2449

S1119 Cabozantinib(XL184, BMS-907351)

Phase 1

Phase 2

S2194 R406

S1244 Amuvatinib (MP-470)

S2692 TG101209

2005

2009

2002

2005

2009

2011

2006

2005

2007


Phase 3

Phase 2

Phase 2

FLT31

c-Kit2

FGFR1/38/9

VEGFR1/2/310/13/8

FLT3wt

4.2

FLT31

c-Kit2

FGFR1/38/9

VEGFR1/2/310/13/8

IC50(nM)

IC50(nM)FLT3ITD

1.1

c-KitD816H

10PDGFRαV561D

40FLT3D835Y

81

JAK26

RET17

JAK3169

FLT325

Abl14

FGFR136

Aurora A48

VEGFR1/2/312/0.035/6

FLT36

FLT3~200

Syk41

IC50(nM)

IC50(nM)

c-Met1.3

Ret4

FLT311.3IC50(nM)

IC50(nM)

IC50(nM)

IC50(nM)


Discov

ery

FLT3 inhibitors

Targets

FLT30.22

PDGFRβ0.20

c-Kit0.17IC50(μM)

Targets

Targets

Targets

Targets

Targets

Targets

Targets

Targets

S2018 ENMD-2076 L-(+)-Tartaric acid

S8023 TCS 359

2010

2006

Aurora A14

VEGFR315.9

VEGFR258.2

FLT31.86

FLT342

IC50(nM)

IC50(nM)

Targets

Targets

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors


KU-0063794PP242

ERK

SB 203580SB 202190


BIRB 796(p38α)LY2228820(p38α)

Pan-p38 inhibitors

Sirtuin

45

S1541 EX 527

S2804 Sirtinol

S1396 Resveratrol Phase 3

2007

2006

2001

2002

S1129 SRT1720

Phase 3

SIRT10.16

SIRT237

SIRT3>300

SIRT219600

SIRT348700

EC1.5(μM)

IC50(nM)SIRT138


Discov

ery

Sirtuin activators & inhibitors

Targets

Targets

SIRT238IC50(μM)

SIRT1131

Targets

Resveratrol is a phytoalexin produced naturally by several plants with anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects.

Ⅰ Ⅱ Ⅲ Ⅳ Ⅴ

Acetate

Acetate Glucose Fatty Acids

Pyruvate Fatty-acg1-CoAS

β-oxidation

2ATP+HCO3+NH3

Fatty Acyl-CoAs

Urea cycle

Glutamate

Carbamoyl Phosphate

Acetyl-CoA

Malate

Succinate

IsocitrateTCA Cycle

α-Ketoglutarate

Oxalacetate Citrate

Fumarate IDH2

SOD2ROS

LCAD

PGC-1αFOXO3FOXO4

LXR p300 YY1

FOXO1

GDH

GDH

ANT2

CPS1

H+ H+ H+ H+

ATP

ADP

ATPADP

Pi

OTC

AceCSH2

HMGCS2KetoneBodies

RosiglitazoneGW501516

CiprofibratePPAR antagonist

GW9662

PPAR agonists

Sirtinol

Selective Sirtuin activatorSRT1720(SIRT1)

EX 527(SIRT1)Selective Sirtuin inhibitor

Pan-Sirtuin inhibitor

ResveratrolPan-Sirtuin activator

FG-4592IOX2

2-Methoxyestradiol

HIF inhibitors NF-κB inhibitorsQNZ


JNJ 26854165RITA


Pifithrin-α

p53 activators


Niclosamide(STAT3)


SIRT4

SIRT3

SIRT1

SIRT1PPARα

HIF1αHIF2 PPARγ

NF-κB

p53STAT3

SIRT4

SIRT5

SIRT3

Selectivity

SIRT1

SIRT1

SIRT3

IAP

46

S2754 AT406 (SM-406)

S7010 GDC-0152

2013

2011

2012

S7015 Birinapant

Phase 1

Phase 1

cIAP1<1

XIAP45

cIAP25.1

XIAP66.4

Kd(nM)

Ki(nM)cIAP11.9


Discov

ery

IAP antagonists

Targets

Targets

ML-IAP-BIR314Ki(nM)

XIAP-BIR328

cIAP2-BIR343

cIAP1-BIR317

Targets

Phase 2

TNFα

TNFR1

IL-1β

IL-1R1

MyD88

IL-1RAcP

LPS

TIRAPMyD88

TLR4

TRAMTRIF

TNFα

TNFR1

CD40L

CD40

TWEAK

Fn14

UbUb

UbUb

UbUb

Ub

UbUb

UbUb

TRADD

TRAF2

TRADDTRADDSam68Sam68Sam68RIPK1

TRAF3

RIPK1

FADD

cIAP1XIAP cIAP2

RIPK3

RIPK1

Bid

FADD

Caspase-8Caspase-8

IκB

Proteasome

degradation

Proteasome

degradation

Cytochrome C

Mitochondria

ChemotherapeuticsIrradiation,GrowthFactor Withdrawal

RIPK1

tBid

NIK

Bcl-XL

SMAC

Apaf-1

UbUb

Ub

p50K48

ReIAp50 ReIA

p100 ReIB

p100processing

Gene Expression

P

p52 ReIB

ApoptosisPro-caspase3/7Pro-caspase9

TRADDTRAF2

RIPK1 TRAF2 TRAF3 TRAF2

LUBAC

TAB2

cIAP1/2

TAK1

p50 ReIA p52 ReIB

P

NEMO

RIPK1

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors

IKK-16BAY 11-7082


IMD 0354(IKKβ)

Pan-IKK inhibitors

BirinapantAT406

GDC-0152

IAP antagonists

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors Caspase activatorsPAC-1


Z-VAD-FMK

Ub

Caspase8

Bcl-2 ML-IAP

XIAP

IκB

IKKα IKKα

Caspase9 Caspase3/7

cIAP1cIAP1/2

IKKα IKKβ P

P

P P

BirinapantAT406

GDC-0152

IAP antagonists

BirinapantAT406

GDC-0152

IAP antagonists

MG-132Bortezomib


Delanzomib


Mdm2

47

Survival Signals(Growth Factors)

Oncogenes(Ras) DNA damage

Response G1 arrest G2 arrest Apoptosis DNA repair

Proteasome

Ubiquitylation

Oncogenes(Myc, E1A) Chemotherapy

14-3-3σ GADD45

Cyclin D Cyclin B1

CKIIp14ARF

p21

Nucleus

Active p53

p53 targets

Bcl-XL Bax NOXAPuma FasApaf-1

E2F-1

ABT-263ABT-737

ObatoclaxTW-37AT101

Bcl-2 inhibitors

JNJ 26854165RITA


Pifithrin-α

p53 activators

CCT128930(Akt2)


GSK690693GDC-0068



OSU-03012PHT-427

NU7441PI-103

PIK-75NU7026

PP-121

DNA-PK inhibitorsKU-55933KU-60019

CP-466722VE-821

BEZ235Wortmannin

ATM/ATR inhibitors

KU-55933KU-60019

CP-466722VE-821

BEZ235Wortmannin

ATM/ATR inhibitors

Nutlin-3NSC-207895

Mdm2 inhibitors

Nutlin-3NSC-207895

Mdm2 inhibitorsPan-CDK inhibitorsPD 0332991(CDK4 & CDK6)


BS-181(CDK7) Survivin inhibitorYM155

ATM

CDK4 CDK1

ATR

Mdm2

PI3K

DNA-PK

Bcl-2

p53

Mdm2

Akt

PDK-1

Survivin

S2678 NSC 207895

S8059 Nutlin-3a

S8065 Nutlin-3b

S4923 NSC 66811

S4924 SL-01

2004

1975

2004

2004

2006

2012

S1061 Nutlin-3 Mdm2 90IC50(nM)

MDMXIC50(μM) 2.5

p53/Mdm2 interactionIC50(nM) 90

Ki(nM)

IC50(μM)

Cat.No. Product Name Information

Discov

ery

Mdm2 inhibitors

Targets

Targets

Targets

Targets

Mdm213.6

Mdm2120

p53/Mdm2 interaction3.18

IC50(μM)Targets

Targets

BEZ235LY294002GDC-0941


GSK2636771(p110β)TGX-221(p110β)

AS-252424(PI3Kγ)CAL-101(p110δ)

Pan-PI3K inhibitors

MG-132Bortezomib


Delanzomib


Headquarters

Order & InquiryToll Free: +1 877 796-6397Tel: +1 832 582-8158Fax: +1 832 582-8590E-mail: [email protected]

Delivery E-mail: [email protected]: +1 713 535-9129

Technical Support Tel: +1 832 582-8158 x3E-mail: [email protected] (We strive to reply to all email inquiries within one business day)

Order & InquiryTel: +49 89 46148500 (Language: English, French, Spanish, German)Fax: +49 89 461485022E-mail: [email protected]

Delivery E-mail: [email protected]

United States Europe

--- Inhibitor Expert (Inhibitors,Modulators,Libraries)

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