TABLE 4.
Interventions in the intracellular compartment
| Intervention | Use | Proposed target | Effect | Affinity | Reference |
|---|---|---|---|---|---|
| 1. Interventions Targeting Disheveled | |||||
| 3289–8625 | In vitro and in vivo (Xenopus embryos and mice) | DVL PDZ | Blockade of DVL → Inhibition of WNT signaling | IC50: 10.5 μM | Grandy et al. (2009) |
| NSC668036 | In silico and in vivo (Xenopys embryos) | DVL PDZ | Blockade of DVL → Inhibition of WNT signaling | n/a | Shan et al. (2005) |
| J01-017a | In silico | DVL PDZ | Blockade of DVL → Inhibition of WNT signaling | n/a | Shan et al. (2012) |
| FJ9 | In vitro and in vivo (mice) | DVL PDZ | FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling | n/a | Fujii et al. (2007) |
| PolyR-DBM | Ex vivo and in vitro | DVL-CXXC5 | FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling | n/a | Kim et al. (2015) |
| KY-02327 | In silico, in vitro, ex vivo, in vivo (mice) | DVL-CXXC5 | FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling | IC50: 3.1 μM | Kim et al. (2016) |
| KY-02061 | In silico, in vitro, ex vivo, in vivo (mice) | DVL-CXXC5 | FZD7-DVL PDZ interaction disruption → Inhibition of WNT signaling | IC50: 24 μM | Kim et al. (2016) |
| pen-N3 | In silico and in vitro | DVL PDZ | Blockade of DVL → Inhibition of WNT signaling | IC50: 11 ± 4 μM | Zhang et al. (2009b) |
| 2. Interventions Targeting Axin | |||||
| XAV939 | In vitro and in vivo (mice) | axin | Induction of protein levels and stabilization of axin → Enhancement of | IC50: 0.114–2.194 μM (PARP1/2); | Huang et al. (2009), Wang et al. (2014a) |
| axin-GSK3β complex formation → Inhibition of Wnt Signaling | IC50: 0.004–0.011 μM (TNKS1/2) | ||||
| IWR-1 and IWR-2 | In vitro and in vivo (zebrafish and mice) | axin | Induction of protein levels and stabilization of axin → Enhancement of | IC50 IWR-1: 0.18 μM; | Chen et al. (2009), Wang et al. (2014a) |
| axin-GSK3β complex formation → Inhibition of Wnt Signaling | IC50 IWR-2: 0.23 μM | ||||
| XAV939 + 5-FU or cisplatin | In vitro | axin | Induction of protein levels and stabilization of axin → Enhancement of | n/a | Wu et al. (2016b) |
| axin-GSK3β complex formation → Inhibition of Wnt Signaling | |||||
| XAV939 + ICAT + niclosamide | In vitro | axin; β-catenin/ | Stabilization of axin (XAV939), β-catenin/p300 complex inhibition (ICAT), | n/a | Ono et al. (2014) |
| p300 complex; FZD1 | FZD1 internalization (niclosamide) → Inhibition of Wnt Signaling | ||||
| E7449 | In vitro and in vivo (mice) | axin/PARPs | TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling | IC50 PARP1/2: 1–2 nM, IC50 TNKS1/2: 50–120 nM | McGonigle et al. (2015) |
| WXL-8 | In vitro and in vivo (mice) | axin/TNKSs | TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling | IC50: 9.1 nM (TNKS1) | Ma et al. (2015) |
| JW67, JW74 and JW55 | In vitro and in vivo (Xenopus embryos and mice) | axin | TNKS proteins inhibition → Induction of protein levels and stabilization of axin → | IC50 JW67: 1.17 mM; IC50 JW64: 790 nM; | Waaler et al. (2011), (2012) |
| Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling | IC50 JW55: 470 nM | ||||
| Compounds 13 and 14 | In silico and in vitro | axin/TNKSs | TNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signaling | IC50 = 2 nM (for TNKs2) | Nathubhai et al. (2017) |
| WIKI4 | In vitro | axin/TNKSs | TNKS proteins inhibition → Halting of axin ubiquitination → | IC50: 15 nM (TNKS2) | James et al. (2012) |
| Stabilization of axin → Inhibition of WNT signaling | |||||
| G007-LK | In vitro and in vivo (mice) | axin/TNKSs | TNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signaling | IC50: 0.08 μM | Lau et al. (2013) |
| AZ1366 + EGFR-inhibitor | In vitro and in vivo (mice) | axin/TNKSs | TNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signaling | n/a | Scarborough et al. (2017) |
| AZ1366 + irinotecanin | In vitro and in vivo (mice) | axin/TNKSs | TNKS proteins inhibition → axin induction → | n/a | Quackenbush et al. (2016) |
| IWRs (1-5) | In vitro and in vivo (zebrafish) | axin/TNKSs | TNKS proteins inhibition → Induction of protein levels and stabilization of axin → | IC50: 0.18–2.0 μM | Chen et al. (2009) |
| Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling | |||||
| NVP-TNKS656 | In silico and in vitro | axin/TNKSs | TNKS proteins inhibition → Induction of protein levels and stabilization of axin → | IC50: 0.006 μM (TNKS2) | Shultz et al. (2013) |
| Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling | |||||
| Compounds 9 and 25 | In silico and in vitro | axin/TNKSs | TNKS proteins inhibition → Induction of protein levels and stabilization of axin → | IC50: <0.003 μM (compound 9:) | Johannes et al. (2015) |
| Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling | IC50: 0.005 μM (Wnt cell) (compound 25) | ||||
| SEN461 | In vitro and in vivo (Xenopus embryos and mice) | axin (not via TNKs?) | Induction of protein levels and stabilization of axin → Enhancement of axin-GSK3β | IC50: 18 μM (TNKS1); IC50: 2.9 μM (TNKS2); | De Robertis et al. (2013) |
| complex formation → Inhibition of Wnt Signaling | IC50: 0.2–1.9 μM (Ca cell assays) | De Robertis et al. (2014) | |||
| Tigecycline (monotherapy or + paclitaxel) | In vitro and in vivo (mice) | axin1 | Induction of protein levels and stabilization of axin1 → Enhancement of axin-GSK3β | n/a | Li et al. (2015) |
| complex formation → Inhibition of Wnt Signaling | |||||
| SKL2001 | In vitro | axin | Disruption of the axin/β-catenin interaction → Activation of Wnt signaling | n/a | Gwak et al. (2012) |
| 3. Interventions Targeting CK1 | |||||
| Pyrvinium | In vitro and in vivo (Xenopus embryo and mice) | CK1 | Induction of CK1α → Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling | n/a | Saraswati et al. (2010), Thorne et al. (2010) |
| CKI-7 | In vitro (Xenopus embryos and C. elegans) | CK1/DVL | Inhibition of CK and DVL → Inhibition of Wnt Signaling | n/a | Peters et al. (1999) |
| IC261 | In vitro | CK1 | Targeting of CK1ε → Inhibition of Wnt Signaling | IC50: 0.5–86 μM (depending on cell line treated) | Kim et al. (2010b) |
| SB203580 | In vitro | CK1 | Targeting of CK1δ/ε → Inhibition of Wnt Signaling | ? | Laco et al. (2015) |
| SR-3029 | In vitro and in vivo (mice) | CK1 | Targeting of CK1δ → Inhibition of Wnt Signaling | n/a | Rosenberg et al. (2015) |
| 4. Interventions Activating GSK3β | |||||
| Curcumin | In vitro | GSK3β | Akt inhibits p-GSK3β → activation of GSK3β → Enhancement of destruction complex → Inhibition of Wnt Signaling | IC50: 25 mM (after 24 hours treatment) and 18.4 mM (after 48 hours treatment) | Choi et al. (2010) |
| 9-Hydroxycanthin-6-one | In vitro and in vivo (zebrafish embryos) | GSK3β | Induction of GSK3β → Inhibition of Wnt Signaling (without involvement of CK) | IC50: 36.7 - > 40 μM (depending on cell line) | Ohishi et al. (2015) |
| All-trans retinoic acid (ATRA) | In vitro | GSK3β | Induction of GSK3β → Inhibition of Wnt Signaling | n/a | Zhu et al. (2015) |
| S-ibuprofen | In vitro | GSK3β | Induction of p-GSK3β → Inhibition of Wnt Signaling (NF-κB also involved) | n/a | Greenspan et al. (2011) |
| 5. Interventions Inhibiting GSK3β | |||||
| Lithium | In vitro | GSK3β (and β-catenin) | Inhibition of GSK3β (+ up-regulation of β-catenin) → Activation of Wnt Signaling | n/a | Wexler et al. (2008) |
| Valproic acid | In vitro | GSK3β | Inhibition of GSK3β → Activation of Wnt Signaling | n/a | Chen et al. (1999) |
| 6-bromoindirubin-3′-oxime (BIO) | In vitro and in vivo (mice) | GSK3β | Competitive inhibition of GSK3β → Activation of Wnt Signaling | n/a | Kohler et al. (2014) |
| In vitro (incl. stem cells) | GSK3β | Inhibition of GSK3β → Activation of Wnt Signaling | n/a | Sato et al. (2004), Wen et al. (2010), Tseng et al. (2006) | |
| IBU-PO | In vitro | GSK3β | Induction of p-GSK3β → Inhibition of GSK3β → Activation of Wnt Signaling | n/a | Farias et al. (2005) |
| Curcumin | In vitro | GSK3β (and axin) | Inhibition of GSK3β (and axin) → Activation of Wnt Signaling | n/a | Ahn et al. (2010) |
| SB-216763 and SB-415286 | In vitro | GSK3α/β | Inhibition of GSK3β → Activation of Wnt Signaling | ID50: 34 nM (SB-216763); IC50: 78 nM (SB-415286) | Coghlan et al. (2000) |
| Kenpaullone | In vitro (stem and progenitor cells) | GSK3 | Inhibition of GSK3 → Activation of Wnt Signaling | n/a | Lange et al. (2011) |
| CHIR 99021 | In vitro (incl. embryonic stem cells) | GSK3α/β | Inhibition of GSK3β → Activation of Wnt Signaling | IC50: 5 nM (GSK3β) | Bennett et al. (2002), Ye et al. (2012), Hou et al. (2013) |
| Naujok et al. (2014) | |||||
| CG0009 | In vitro | GSK3β | Induction of Ser9 p-GSK3β and inhibition of Tyr215 p-GSK3β → Inhibition of GSK3β →Activation of Wnt Signaling | IC50: 0.49–>100 μM (depending on cell type in the assay) | Kim et al. (2013) |
| L803-mts | In vitro and in vivo (mice) | GSK3 | Inhibition of GSK3 → Activation of Wnt Signaling | IC50: 40 μM | Plotkin et al. (2003), Kaidanovich-Beilin et al. (2004) |