Chen B, Dodge ME, Tang W et al.Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100-107

Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Nature Chemical Biology (Impact Factor: 13). 01/2009; 5(2):100-107. DOI: 10.1038/nchembio.137


The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.

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    • "Disruption of Fgf signalling, for example by inactivation of the fibroblast growth factor receptor 1 (Fgfr1) gene, blocks blastema formation and expression of the homeobox domain gene msxb which marks the cells in the distal part of the blastema (Akimenko et al., 1995; Lee et al., 2005; Thummel et al., 2006). Inhibition of Wnt/bcatenin signalling also prevents the early specification of the distal blastema (Stoick-Cooper et al., 2007; Chen et al., 2009; Wehner et al., 2014). Both pathways have been reported to be involved in all stages of regeneration from wound closure to regenerative outgrowth. "
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    • "This is in agreement with the primary function of RAB8B in ligand-receiving cells (Demir et al., 2013). Stronger inhibitory effects on Wnt3a-Gluc secretion were observed upon treatment with C59 (∼93% reduction), a Porcupine inhibitor (Chen et al., 2009), or by Gpr177 ablation in MEFs (∼97% reduction) (Fig. 2C). Notably, Fig. 2. Rab8a deletion reduces Wnt secretion. "
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    • "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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