Interventions in β-catenin and gene transcription
| Intervention | Use | Proposed target | Effect | Affinity | Reference |
|---|---|---|---|---|---|
| 1. Targeting of the TCF/LEF Transcription Factors | |||||
| iCRT3, iCRT5 and iCRT14 | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling | IC50: 8.2 nM (iCRT3); IC50: 18.7 nM (iCRT5); IC50: 40.3 nM (iCRT14) - in STF16 luciferase assay | Gonsalves et al. (2011), Griffiths et al. (2015) |
| Thiazole and oxazole | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Narayanan et al. (2012) |
| 15-oxospiramilactone (NC043) | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | IC50: 0.9–6.9 μM (depending on the cell type) | Wang et al. (2011b) |
| Henryin | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | IC50: 0.6 ± 0.02 μM (ST-luciferase assay) | Li et al. (2013c) |
| 11α,12α-epoxyleukamenin E (EPLE) | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Ye et al. (2015) |
| LF3 | In silico, in vitro and in vivo (mice) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | IC50: 2.4–4.0 mM (HeLa cells); IC50: 22.2 ± 4.9 mM (HEK293 TOPFlash assay) | Fang et al. (2016) |
| BC-21 | In silico and in vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | IC50: 5 μM (β-catenin-TCF4 inhibition assay) | Tian et al. (2012) |
| BC-23 (monotherapy or with radiation therapy) | In silico and in vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | IC50: 5 μM (β-catenin-TCF4 inhibition assay) | Zhang et al. (2016a) |
| PNU-74654 | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling | IC50: 117.2–5026.0 μM (depending on time and cell line used in the assay) | Leal et al. (2015) |
| PKF115-584 | In vitro and in vivo (Xenopus embryos) In vitro and in vivo (mice) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction, TCF binding with DNA, β-catenin/APC complex formation and antagonism of exogenous β-catenin → Inhibition of WNT Signaling | IC50: 3.2 μM (β-catenin - TCF4 inhibition assay) IC50: 0.31–2.05 μM (sphere forming assay, range depending on cell type) | Lepourcelet et al. (2004), Hallett et al. (2012) |
| CGP049090 | In vitro and in vivo (Xenopus embryos) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction, TCF binding with DNA, β-catenin/APC complex formation and antagonism of exogenous β-catenin → Inhibition of WNT Signaling | IC50: 8.7 μM (β-catenin-TCF4 inhibition assay) | Lepourcelet et al. (2004) |
| PKF222-815 | In vitro and in vivo (Xenopus embryos) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction and antagonism of exogenous β-catenin → Inhibition of WNT Signaling | IC50: 4.1 μM (β-catenin - TCF4 inhibition assay) | Lepourcelet et al. (2004) |
| PKF118–310 | In vitro and in vivo (mice) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction and antagonism of exogenous β-catenin → Inhibition of WNT Signaling | IC50: 0.8 μM (β-catenin-TCF4 inhibition assay) | Lepourcelet et al. (2004) |
| In vitro and in vivo (mice) | IC50: 0.54–1.54 μM (sphere forming assay, range depending on cell type) | Hallett et al. (2012) | |||
| Daxx | In vitro | β-catenin-TCF/LEF complex | Binding to TCF4 → Potentiation of β-catenin/TCF4-mediated transcriptional activation → Activation of WNT Signaling | n/a | Huang and Shih (2009) |
| Quercetin | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Park et al. (2005) |
| Isoquercitrin | In vitro and in vivo (Xenopus embryos) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF interaction → Inhibition of WNT Signaling | n/a | Amado et al. (2014) |
| 6,7-dihydroxycoumarin (Aesculetin) | In vitro and in vivo (Xenopus embryos and mice) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Lee et al. (2013) |
| Curcumin | In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Jaiswal et al., 2002 |
| In vitro | β-catenin-TCF/LEF complex | Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Teiten et al. (2011) | |
| Aspirin | In vitro | β-catenin-TCF gene transcription | Suppression of gene transcription of β-catenin/TCF4 → Inhibition of WNT Signaling | n/a | Dihlmann et al. (2001) |
| Indomethacin | In vitro | β-catenin-TCF gene transcription | Suppression of gene transcription of β-catenin/TCF4 → Inhibition of WNT Signaling | n/a | Dihlmann et al. (2001) |
| Celecoxib and 2,5-dimethyl-celecoxib | In vivo (mice) | β-catenin and TCF4 expression | Suppression of β-catenin and TCF4 expression (not clear if the complex formation itself is affected) → Inhibition of TCF-mediated transcription → Inhibition of WNT Signaling | n/a | Fan et al. (2011), Egashira et al. (2017) |
| Sulindac | In vitro and in vivo (mice) | TCF gene transcription | Suppression of gene transcription of TCF → Inhibition of WNT Signaling | IC50: 1.8–33.9 μM (for COX-1/2 and cGMP) | Tinsley et al. (2010) |
| In vitro | β-catenin and TCF4 expression | Suppression of gene transcription of TCF and β-catenin synthesis → Inhibition of WNT Signaling | IC50: 75–83 μM (following 72 hour treatment of various human cancer cell lines) | Li et al. (2013) | |
| ICAT | In vitro and in vivo (Xenopus embryos) | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Tago et al. (2000) |
| In vitro | β-catenin-TCF/LEF complex | Interference with the β-catenin/TCF/LEF interaction → Inhibition of WNT Signaling | n/a | Daniels and Weis (2002) | |
| 2. Targeting of CBP | |||||
| ICG-001 (PRI-724) | In vitro, in vivo (mice) and CT | CBP | Disruption of the β-catenin/CBP interaction → Inhibition of WNT Signaling | IC50: 3 μM (TOPFlash assay) | Emami et al. (2004), Henderson et al. (2010), El-Khoueiry et al. (2013), Sasaki et al. (2013) |
| PMED-1 | In silico and in vitro | CBP | Disruption of the β-catenin/CBP interaction → Inhibition of WNT Signaling | IC50: 4.87–32 μM (depending on cell type in the TOPFlash assay) | Delgado et al. (2014) |
| Curcumin | In vitro | CBP | Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Teiten et al. (2011) |
| 3. Targeting of p300 | |||||
| ICAT | In vitro | p300 | Inhibition of the β-catenin/Lef1/p300 interaction → Inhibition of WNT Signaling | n/a | Daniels and Weis (2002) |
| ICAT-61 (helical domain of ICAT) | In vitro | p300 | Disruption of the β-catenin/p300 interaction (but no interference with the binding of TCF/LEF) → Inhibition of WNT Signaling | n/a | Daniels and Weis (2002) |
| Windorphen (WD) | In vitro and in vivo (Zebrafish embryos) | p300 | Disruption of the β-catenin/p300 interaction → Inhibition of WNT Signaling | IC50: 4.2 μM (p300); IC50: 1.5 μM (WNT3a-inducible TOPFlash assay) | Hao et al. (2013) |
| IQ1 | In vitro and in vivo (mice) | p300 | Disruption of the β-catenin/p300 interaction → Amplification of the β-catenin/TCF4 interaction → Activation of WNT Signaling (paradox?) | n/a | Sasaki and Kahn (2014) |
| Bisdemethoxycurcumin (BDMC) and demethoxycurcumin (DMC) | In vitro | p300 | Downregulation of p300 (without effects on TCF4 or β-catenin levels) → Inhibition of WNT Signaling | n/a | Ryu et al. (2008) |
| Curcumin | In vitro | p300 | Decrease of TCF4, CBP and p300 protein levels → Interference with the β-catenin/TCF4 interaction → Inhibition of WNT Signaling | n/a | Teiten et al. (2011) |
| 4. Targeting of BCL9 | |||||
| Carnosic acid (CA) | In silico and in vitro | β-catenin/BCL9 complex | Interference with β-catenin/BCL9 interaction and degradation of β-catenin → Inhibition of WNT Signaling | n/a | de la Roche et al. (2012) |
| In silico and in vitro | β-catenin/BCL9 complex | Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling | IC50: 8.7 ± 1.5–20 ± 0.18 μM (depending on cell line) | Hoggard et al. (2015) | |
| LATS Large Tumor Suppressor (LATS) 2 | In vitro and in vivo (mice) | β-catenin/BCL9 complex | Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling | n/a | Li et al. (2013) |
| Compound 11 | In silico and in vitro | β-catenin/BCL9 complex | Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling | IC50: 22 ± 4.0–26 ± 6.6 μM (depending on cell line) | Wisniewski et al. (2016) |
| SAH-BCL9 | In vitro and in vivo (mice) | β-catenin/BCL9 complex | Interference with β-catenin/BCL9 interaction → Inhibition of WNT Signaling | IC50: 135–810 nM (depending on assay) | Takada et al. (2012) |