Small-molecule inhibition of Wnt signaling through activation of casein kinase 1alpha. Nat Chem Biol 6:829-836

Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nature Chemical Biology (Impact Factor: 13). 10/2010; 6(11):829-36. DOI: 10.1038/nchembio.453
Source: PubMed


Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of ∼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.

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Available from: Curtis Thorne, Jul 09, 2014
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    • "Due to the involvement of several proteins and protein complexes, it is possible to inhibit this pathway at different levels [11]. Some recently published small molecules that target the Wnt pathway are reported in Fig. 1 and encompass casein kinase 1a (CK1a) activators [13] (as pyrvinium pamoate), porcupine inhibitors [14e16] (IWP-1, IWP-2, IWP-L6, LGK974), inhibitors of frizzled-Wnt interaction [17] (niclosamide), inhibitors of the PDZ domain of disheveled [18e20] (3289-8625, sulindac, J01-017a) and tankyrase (TNKS) inhibitors. Since TNKS were described as a promising target to antagonize Wnt/b-catenin signaling, several research groups have concentrated their efforts in the identification of new inhibitors, some examples are XAV939 [21], IWR-1 [14 above], IWR-2 [14], IWR-3 [14], JW55 [22], JW67 [23], JW74 [23], G007-LK [24], WIKI4 [25], NVP-TNKS656 [26], series of oxazolidinones [27] [28] and flavones [29]. "
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    ABSTRACT: Wnt signaling pathway plays a critical role in numerous cellular processes, including tumor initiation, proliferation, invasion/infiltration, metastasis formation and resistance to chemotherapy. In a drug discovery project aimed at the identification of inhibitors of the canonical Wnt pathway, we selected a series of quinazoline 2,4-diones as starting point for the therapeutic treatment of glioblastoma multiforme. Despite of poor physico-chemical properties of hit compound 1, our medicinal chemistry effort allowed the discovery and characterization of lead compound 33 (SEN461), with improved ADME profile, good bioavailability and active in vitro and in vivo in glioblastoma, gastric and sarcoma tumors. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Full-text · Article · May 2015 · European Journal of Medicinal Chemistry
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    • "We observed that during 60 min of continuous perfusion of pyrvinium pamoate (20 nM) there is a strong and constant reduction in the spiking activity in CA3, and simultaneously, a significant increase in the same parameter in CA1 (Figs. 5C–D). The potency of this effect, the strongest we observed, could be explained by the fact that pamoate keeps the CK-1α active, avoiding any accumulation of β-catenin into the cell (Hernandez et al., 2012; Liu et al., 2002; Thorne et al., 2010). Interestingly, these experiments show that the firing activity in CA3 strongly depends on the activation of Wnt/β-catenin dependent signaling, unlike CA1, which seems to be independent of Wnt/β-catenin pathway (Fig. 5D). "
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    ABSTRACT: During early and late postnatal development, the establishment of functional neuronal connectivity depends on molecules like Wnt that help the recently formed synapses to establish and consolidate their new cellular interactions. However, unlike other molecules, whether Wnt can modulate the firing properties of cells is unknown. Here, for the first time we explore the physiological effect of the canonical and non-canonical Wnt pathways on a circuit that is currently generating oscillatory activity, the entorhinal cortex-hippocampal circuit. Our results indicate that Wnt pathways have strong influence in the circuital and cellular properties depending on the Wnt protein isoforms, concentration, and type of neuronal circuit. Antibodies against canonical and non-canonical ligands, as well as WASP-1 and sFRP-2, demonstrate that constitutive release of Wnts contributes to the maintenance of the network and intrinsic properties of the circuit. Furthermore, we found that the excess of Wnt3a or the permanent intracellular activation of the pathway with BIO-6 accelerates the period of the oscillation by disrupting the oscillatory units (Up states) in short units, presumably by affecting the synaptic mechanisms that couples neurons into the oscillatory cycle, but without affecting the spike generation. Instead, low doses of Wnt5a increases the period of the oscillation in EC by incorporating new cells into the network activity, probably modifying firing activity in other places of the circuit. Moreover, we found that Wnt signaling operates under different principles in hippocampus. Using pyrvinium pamoate, a Wnt/β-catenin dependent pathway inhibitor, we demonstrated that this pathway is essential to keep the firing activity in the circuit CA3, and in less degree of CA1 circuit. However, CA1 circuit possesses homeostatic mechanisms to up-regulate the firing activity when has been suppressed in CA3, and to down-modulate the cellular excitability when exacerbated circuital activity has dominated. In summary, the amount of Wnt that is being released can exert a fine tuning of the physiological output, modulating firing activity, improving reliability of communication between neurons, and maintaining a continuous self-regulatory cycle of synaptic structure-function that can be present during all postnatal life. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Experimental Neurology
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    • "* represents statistical significance at p<0.05 compared against control as determined by one-way ANOVA Bangladesh J Pharmacol 2015; 10: 47-56 51 to be potential for treating colorectal cancers. In this regard, small molecules like flavonoids synthesized or from natural origin, have been identified as potential modulators of Wnt/-catenin signaling pathway (Sarkar et al., 2009; Thorne et al., 2010). "
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    ABSTRACT: Colorectal cancer is one of the leading causes of death worldwide. Wnt/beta catenin signalling pathway plays a central role in normal cellular responses, making it a potent target in cancer therapy. Study was taken to assess whether ellagic acid modulates Wnt/beta-catenin pathway and CDK8 activity in colon cancer cells (HT 29 and HCT 116). Ellagic acid caused significant decrease in viability of cancer cells and markedly down-regulated the expression of CDK 8, beta-catenin, survivin, c-Myc and cyclin D1. siCDK8 transfection resulted in marked reduction in the expression of survivin, c-Myc and cyclin D1 as well. Considerable up-regulation in the expression of p-beta-catenin, axin1 and 2 following ellagic acid exposure were observed. Ellagic acid was able to effectively reduce cell viability and modulate expressions of Wnt/beta-catenin signalling cascade proteins and down regulate the activity and expression of CDK8 in HT 29 and HCT 116 cells.
    Preview · Article · Jan 2015 · Bangladesh Journal of Pharmacology
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