TABLE 4

Interventions in the intracellular compartment

InterventionUseProposed targetEffectAffinityReference
1. Interventions Targeting Disheveled
3289–8625In vitro and in vivo (Xenopus embryos and mice)DVL PDZBlockade of DVL → Inhibition of WNT signalingIC50: 10.5 μMGrandy et al. (2009)
NSC668036In silico and in vivo (Xenopys embryos)DVL PDZBlockade of DVL → Inhibition of WNT signalingn/aShan et al. (2005)
J01-017aIn silicoDVL PDZBlockade of DVL → Inhibition of WNT signalingn/aShan et al. (2012)
FJ9In vitro and in vivo (mice)DVL PDZFZD7-DVL PDZ interaction disruption → Inhibition of WNT signalingn/aFujii et al. (2007)
PolyR-DBMEx vivo and in vitroDVL-CXXC5FZD7-DVL PDZ interaction disruption → Inhibition of WNT signalingn/aKim et al. (2015)
KY-02327In silico, in vitro, ex vivo, in vivo (mice)DVL-CXXC5FZD7-DVL PDZ interaction disruption → Inhibition of WNT signalingIC50: 3.1 μMKim et al. (2016)
KY-02061In silico, in vitro, ex vivo, in vivo (mice)DVL-CXXC5FZD7-DVL PDZ interaction disruption → Inhibition of WNT signalingIC50: 24 μMKim et al. (2016)
pen-N3In silico and in vitroDVL PDZBlockade of DVL → Inhibition of WNT signalingIC50: 11 ± 4 μMZhang et al. (2009b)
2. Interventions Targeting Axin
XAV939In vitro and in vivo (mice)axinInduction of protein levels and stabilization of axin → Enhancement ofIC50: 0.114–2.194 μM (PARP1/2);Huang et al. (2009), Wang et al. (2014a)
axin-GSK3β complex formation → Inhibition of Wnt SignalingIC50: 0.004–0.011 μM (TNKS1/2)
IWR-1 and IWR-2In vitro and in vivo (zebrafish and mice)axinInduction of protein levels and stabilization of axin → Enhancement ofIC50 IWR-1: 0.18 μM;Chen et al. (2009), Wang et al. (2014a)
axin-GSK3β complex formation → Inhibition of Wnt SignalingIC50 IWR-2: 0.23 μM
XAV939 + 5-FU or cisplatinIn vitroaxinInduction of protein levels and stabilization of axin → Enhancement ofn/aWu et al. (2016b)
axin-GSK3β complex formation → Inhibition of Wnt Signaling
XAV939 + ICAT + niclosamideIn vitroaxin; β-catenin/Stabilization of axin (XAV939), β-catenin/p300 complex inhibition (ICAT),n/aOno et al. (2014)
p300 complex; FZD1FZD1 internalization (niclosamide) → Inhibition of Wnt Signaling
E7449In vitro and in vivo (mice)axin/PARPsTNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signalingIC50 PARP1/2: 1–2 nM, IC50 TNKS1/2: 50–120 nMMcGonigle et al. (2015)
WXL-8In vitro and in vivo (mice)axin/TNKSsTNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signalingIC50: 9.1 nM (TNKS1)Ma et al. (2015)
JW67, JW74 and JW55In vitro and in vivo (Xenopus embryos and mice)axinTNKS 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 SignalingIC50 JW55: 470 nM
Compounds 13 and 14In silico and in vitroaxin/TNKSsTNKS proteins inhibition → Stabilization of axin → Inhibition of Wnt signalingIC50 = 2 nM (for TNKs2)Nathubhai et al. (2017)
WIKI4In vitroaxin/TNKSsTNKS proteins inhibition → Halting of axin ubiquitination →IC50: 15 nM (TNKS2)James et al. (2012)
Stabilization of axin → Inhibition of WNT signaling
G007-LKIn vitro and in vivo (mice)axin/TNKSsTNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signalingIC50: 0.08 μMLau et al. (2013)
AZ1366 + EGFR-inhibitorIn vitro and in vivo (mice)axin/TNKSsTNKS proteins inhibition → Stabilization of axin → Inhibition of WNT signalingn/aScarborough et al. (2017)
AZ1366 + irinotecaninIn vitro and in vivo (mice)axin/TNKSsTNKS proteins inhibition → axin induction →n/aQuackenbush et al. (2016)
IWRs (1-5)In vitro and in vivo (zebrafish)axin/TNKSsTNKS proteins inhibition → Induction of protein levels and stabilization of axin →IC50: 0.18–2.0 μMChen et al. (2009)
Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signaling
NVP-TNKS656In silico and in vitroaxin/TNKSsTNKS 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 25In silico and in vitroaxin/TNKSsTNKS 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 SignalingIC50: 0.005 μM (Wnt cell) (compound 25)
SEN461In vitro and in vivo (Xenopus embryos and mice)axin
(not via TNKs?)Induction of protein levels and stabilization of axin → Enhancement of axin-GSK3βIC50: 18 μM (TNKS1); IC50: 2.9 μM (TNKS2);De Robertis et al. (2013)
complex formation → Inhibition of Wnt SignalingIC50: 0.2–1.9 μM (Ca cell assays)De Robertis et al. (2014)
Tigecycline
(monotherapy or + paclitaxel)In vitro and in vivo (mice)axin1Induction of protein levels and stabilization of axin1 → Enhancement of axin-GSK3βn/aLi et al. (2015)
complex formation → Inhibition of Wnt Signaling
SKL2001In vitroaxinDisruption of the axin/β-catenin interaction → Activation of Wnt signalingn/aGwak et al. (2012)
3. Interventions Targeting CK1
PyrviniumIn vitro and in vivo (Xenopus embryo and mice)CK1Induction of CK1α → Enhancement of axin-GSK3β complex formation → Inhibition of Wnt Signalingn/aSaraswati et al. (2010), Thorne et al. (2010)
CKI-7In vitro (Xenopus embryos and C. elegans)CK1/DVLInhibition of CK and DVL → Inhibition of Wnt Signalingn/aPeters et al. (1999)
IC261In vitroCK1Targeting of CK1ε → Inhibition of Wnt SignalingIC50: 0.5–86 μM (depending on cell line treated)Kim et al. (2010b)
SB203580In vitroCK1Targeting of CK1δ/ε → Inhibition of Wnt Signaling?Laco et al. (2015)
SR-3029In vitro and in vivo (mice)CK1Targeting of CK1δ → Inhibition of Wnt Signalingn/aRosenberg et al. (2015)
4. Interventions Activating GSK3β
CurcuminIn vitroGSK3βAkt inhibits p-GSK3β → activation of GSK3β → Enhancement of
destruction complex → Inhibition of Wnt SignalingIC50: 25 mM (after 24 hours treatment) and
18.4 mM (after 48 hours treatment)Choi et al. (2010)
9-Hydroxycanthin-6-oneIn vitro and in vivo (zebrafish embryos)GSK3βInduction 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 vitroGSK3βInduction of GSK3β → Inhibition of Wnt Signalingn/aZhu et al. (2015)
S-ibuprofenIn vitroGSK3βInduction of p-GSK3β → Inhibition of Wnt Signaling
(NF-κB also involved)n/aGreenspan et al. (2011)
5. Interventions Inhibiting GSK3β
LithiumIn vitroGSK3β
(and β-catenin)Inhibition of GSK3β (+ up-regulation of β-catenin) → Activation of Wnt Signalingn/aWexler et al. (2008)
Valproic acidIn vitroGSK3βInhibition of GSK3β → Activation of Wnt Signalingn/aChen et al. (1999)
6-bromoindirubin-3′-oxime
(BIO)In vitro and in vivo (mice)GSK3βCompetitive inhibition of GSK3β → Activation of Wnt Signalingn/aKohler et al. (2014)
In vitro (incl. stem cells)GSK3βInhibition of GSK3β → Activation of Wnt Signalingn/aSato et al. (2004), Wen et al. (2010), Tseng et al. (2006)
IBU-POIn vitroGSK3βInduction of p-GSK3β → Inhibition of GSK3β → Activation of Wnt Signalingn/aFarias et al. (2005)
CurcuminIn vitroGSK3β
(and axin)Inhibition of GSK3β (and axin) → Activation of Wnt Signalingn/aAhn et al. (2010)
SB-216763 and SB-415286In vitroGSK3α/βInhibition of GSK3β → Activation of Wnt SignalingID50: 34 nM (SB-216763); IC50: 78 nM (SB-415286)Coghlan et al. (2000)
KenpaulloneIn vitro (stem and progenitor cells)GSK3Inhibition of GSK3 → Activation of Wnt Signalingn/aLange et al. (2011)
CHIR 99021In vitro (incl. embryonic stem cells)GSK3α/βInhibition of GSK3β → Activation of Wnt SignalingIC50: 5 nM (GSK3β)Bennett et al. (2002), Ye et al. (2012), Hou et al. (2013)
Naujok et al. (2014)
CG0009In vitroGSK3βInduction of Ser9 p-GSK3β and inhibition of Tyr215 p-GSK3β → Inhibition of GSK3β →Activation of Wnt SignalingIC50: 0.49–>100 μM (depending on cell type in the assay)Kim et al. (2013)
L803-mtsIn vitro and in vivo (mice)GSK3Inhibition of GSK3 → Activation of Wnt SignalingIC50: 40 μMPlotkin et al. (2003), Kaidanovich-Beilin et al. (2004)