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. 2020 Feb 5;111(3):783–794. doi: 10.1111/cas.14297

Table 1.

Inhibitors of Wnt/β‐catenin signaling discovered by high‐throughput screening (HTS)

Chemical probe HTS assay Cells (condition) Library Mode of action Parameters of RO5 Structure References
IWR‐1 Luciferase reporter (SuperTOPFlash) Mouse L cells (Wnt3a‐CM) 198 080 (UTSouthwestern chemical library) Tankyrase inhibition

MWT = 409.45

CLog P = 2.522

H‐bond donors = 1

H‐bond acceptors = 4

 graphic file with name CAS-111-783-g004.jpg 33
XAV939 Luciferase reporter (SuperTOPFlash) HEK293 N/A Tankyrase inhibition

MWT = 312.31

CLog P = 3.82964

H‐bond donors = 1

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g005.jpg 34
JW74 Fluorescence imaging (SuperTOP‐d1EGFP) HEK293 (Wnt3a‐CM) 37 000 Tankyrase inhibition

MWT = 456.52

CLog P = 4.05445

H‐bond donors = 0

H‐bond acceptors = 6

 graphic file with name CAS-111-783-g006.jpg 30
WIKI4 Luciferase reporter (BAR, TCF reporter) A375 (Wnt3a‐CM) 6492 (KINASet library, Chembridge) Tankyrase inhibition

MWT = 521.60

CLog P = 5.21344

H‐bond donors = 0

H‐bond acceptors = 6

 graphic file with name CAS-111-783-g007.jpg 35
K‐756 Luciferase reporter (TCF reporter) DLD‐1 N/A Tankyrase inhibition

MWT = 433.51

CLog P = 3.4062

H‐bond donors = 1

H‐bond acceptors = 5

 graphic file with name CAS-111-783-g008.jpg 36
IWP‐2 Luciferase reporter (SuperTOPFlash) Mouse L cells (Wnt3a‐CM) 198 080 (UTSouthwestern chemical library) Porcupine inhibition

MWT = 466.59

CLog P = 4.94517

H‐bond donors = 1

H‐bond acceptors = 4

 graphic file with name CAS-111-783-g009.jpg 33
LGK974 Luciferase reporter (SuperTOPFlash) TM3 cells (co‐cultured with L‐cell Wnt3A) ~2 400 000 Porcupine inhibition

MWT = 396.45

CLog P = 1.77295

H‐bond donors = 1

H‐bond acceptors = 6

 graphic file with name CAS-111-783-g010.jpg 38
Pyrvinium pamoate Luciferase reporter (β‐catenin‐Fluc/Axin‐RLuc fusion proteins) Xenopus egg extracts (LRP6ICD) FDA‐approved drug library etc Activation of CK1α

MWT = 382.53

CLog P = 2.78575

H‐bond donors = 0

H‐bond acceptors = 0

 graphic file with name CAS-111-783-g011.jpg 41
ICG‐001 Luciferase reporter (TOPFlash) SW480 5000 Inhibition of β‐catenin‐CBP interaction

MWT = 548.64

CLog P = 6.13165

H‐bond donors = 2

H‐bond acceptors = 4

 graphic file with name CAS-111-783-g012.jpg 54
PKF115‐584 ELISA (β‐catenin/ GST‐TCF4 recombinant proteins) N/A 7000 (natural compounds library) Inhibition of β‐catenin‐TCF interaction

MWT = 790.77

CLog P = 6.87757

H‐bond donors = 3

H‐bond acceptors = 11

 graphic file with name CAS-111-783-g013.jpg 44
iCRT14 Luciferase reporter (TCF reporter) Drosophila Cl8 cells (dAxin‐dsRNA) 14 977 (ICCB‐Longwood collection, Harvard) Inhibition of β‐catenin‐TCF interaction

MWT = 375.45

CLog P = 5.70349

H‐bond donors = 0

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g014.jpg 26
NC043 Luciferase reporter (TOPFlash)

HEK293T

(Wnt1 overexpression, Wnt3a‐CM, or LiCl)

 4000 Indirect inhibition of β‐catenin‐TCF interaction

MWT = 330.42

CLog P = 1.2362

H‐bond donors = 1

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g015.jpg 48
Niclosamide Luciferase reporter (S1004A4 promoter reporter) HCT116 1280 (LOPAC Sigma‐Aldrich) Inhibition of formation of β‐catenin/TCF complex

MWT = 327.12

CLog P = 4.34465

H‐bond donors = 2

H‐bond acceptors = 2

 graphic file with name CAS-111-783-g016.jpg 47
ZINC02092166 Fluorescence polarization and AlphaScreen assays (β‐catenin/fluorescein‐TCF4 recombinant proteins) N/A 2093 (Sigma‐Aldrich, Pfizer, NCI etc) Inhibition of β‐catenin‐TCF interaction

MWT = 349.27

CLog P = 3.91846

H‐bond donors = 2

H‐bond acceptors = 8

 graphic file with name CAS-111-783-g017.jpg 45
LF3 AlphaScreen assay (GST‐β‐catenin/His‐TCF4 recombinant proteins) N/A 16 671 (WDI compounds, ChemBioNet) Inhibition of β‐catenin‐TCF interaction

MWT = 416.56

CLog P = 2.582

H‐bond donors = 2

H‐bond acceptors = 4

 graphic file with name CAS-111-783-g018.jpg 46
Hexachlorophene Luciferase reporter (TOPFlash) HEK293 expressing hFz‐1 (Wnt3a‐CM) 960 (Genesis Plus Collection, MicroSource Discovery) β‐Catenin degradation through SIAH‐1 induction

MWT = 406.89

CLog P = 7.02708

H‐bond donors = 2

H‐bond acceptors = 2

 graphic file with name CAS-111-783-g019.jpg 56
Axitinib Luciferase reporter (SuperTOPFlash) HEK293FT (GSK‐3 inhibitor, 6BIO) 460 (FDA‐approved drug library) β‐Catenin degradation through SHPRH stabilization

MWT = 386.47

CLog P = 3.3269

H‐bond donors = 3

H‐bond acceptors = 4

 graphic file with name CAS-111-783-g020.jpg 58
CGK062 Luciferase reporter (TOPFlash) HEK293 expressing hFz‐1 (Wnt3a‐CM) 800 β‐Catenin degradation through PKCα activation

MWT = 408.41

CLog P = 3.75537

H‐bond donors = 2

H‐bond acceptors = 5

 graphic file with name CAS-111-783-g021.jpg 59
SEN461 Luciferase reporter (TCF reporter) DBTRG.05MG 16 000 (Siena Biotech internal compounds collection) β‐Catenin degradation through Axin stabilization

MWT = 486.57

CLog P = 2.0554

H‐bond donors = 0

H‐bond acceptors = 6

 graphic file with name CAS-111-783-g022.jpg 60
CCT031374 Luciferase reporter (TCF reporter) HEK293 expressing Dvl2‐ER (Disheveled‐estrogen receptor fusion) 63 040 (The Cancer Research UK Center for Cancer Therapeutics compound library) β‐Catenin degradation + unknown mechanism

MWT = 353.43

CLog P = 4.5174

H‐bond donors = 0

H‐bond acceptors = 2

 graphic file with name CAS-111-783-g023.jpg 25
MSAB Luciferase reporter (TOPFlash) HCT116 22 000 (Chembridge and Broad Institute) β‐Catenin binding and degradation

MWT = 305.35

CLog P = 3.405

H‐bond donors = 1

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g024.jpg 61
KY1220 Luciferase reporter (TOPFlash) HEK293 (Wnt3a‐CM) ~3599 (Chemdiv and Sigma LOPAC 1280) Axin binding and β‐catenin degradation

MWT = 314.32

CLog P = 1.60552

H‐bond donors = 2

H‐bond acceptors = 2

 graphic file with name CAS-111-783-g025.jpg 62
FH535 SEAP reporter (TOPFlash) HepG2 11 600 (DIVERSet collection, ChemBridge) Repression of β‐catenin recruitment

MWT = 361.19

CLog P = 3.95088

H‐bond donors = 1

H‐bond acceptors = 2

 graphic file with name CAS-111-783-g026.jpg 29
GGTI‐286 Eye phenotype Zebrafish embryos (GSK‐3 inhibitor, 6BIO) 282 (SCADS inhibitor kit) Inhibition of nuclear accumulation of β‐catenin

MWT = 429.58

CLog P = 3.4042

H‐bond donors = 3

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g027.jpg 63
Brefeldin A Luciferase reporter (TOPFlash and HAL promoter reporter) HepG2 361 (SCADS inhibitor kit) Repression of β‐catenin mRNA

MWT = 280.36

CLog P = .538999

H‐bond donors = 2

H‐bond acceptors = 3

 graphic file with name CAS-111-783-g028.jpg 23

Chemical structures were drawn using ChemDraw. The molecular weights (MWT), calculated octanol/water partition coefficient (CLog P) values, and number of hydrogen bond donors and acceptors were calculated using ChemDraw or Molecular Operating Environment (MOE).

BAR, β‐catenin‐activated reporter; CBP, CREB‐binding protein; CK1α, casein kinase‐1α; GSK‐3, glycogen synthase kinase‐3; N/A, not available; PKCα, protein kinase Cα; SCADS, Screening Committee of Anticancer Drugs; SEAP, secreted alkaline phosphate; TCF, T‐cell factor.