Article

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

ABSTRACT

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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    • "This procedure is based on a 1-day co-stimulation of mesoderminducing pathways at moderate doses. In a second stage, WNT signaling is blocked on days 2–3 using the small molecule inhibitor IWP-2 (Figure 1A; Chen et al., 2009). This treatment promoted the exit from self-renewal and the sequential induction of mesoderm by days 1–2, formation of a putative cardiac precursor cell identity by day 4, and, from day 5 onward, induction of an early cardiomyocyte-like fate (Figures 1B and 1C; Paige et al., 2012). "

    Full-text · Dataset · Jan 2016
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    • "This procedure is based on a 1-day co-stimulation of mesoderminducing pathways at moderate doses. In a second stage, WNT signaling is blocked on days 2–3 using the small molecule inhibitor IWP-2 (Figure 1A; Chen et al., 2009). This treatment promoted the exit from self-renewal and the sequential induction of mesoderm by days 1–2, formation of a putative cardiac precursor cell identity by day 4, and, from day 5 onward, induction of an early cardiomyocyte-like fate (Figures 1B and 1C; Paige et al., 2012). "
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    ABSTRACT: Cardiac induction requires stepwise integration of BMP and WNT pathway activity. Human embryonic stem cells (hESCs) are developmentally and clinically relevant for studying the poorly understood molecular mechanisms downstream of these cascades. We show that BMP and WNT signaling drive cardiac specification by removing sequential roadblocks that otherwise redirect hESC differentiation toward competing fates, rather than activating a cardiac program per se. First, BMP and WNT signals pattern mesendoderm through cooperative repression of SOX2, a potent mesoderm antagonist. BMP signaling promotes miRNA-877 maturation to induce SOX2 mRNA degradation, while WNT-driven EOMES induction transcriptionally represses SOX2. Following mesoderm formation, cardiac differentiation requires inhibition of WNT activity. We found that WNT inhibition serves to restrict expression of anti-cardiac regulators MSX1 and CDX2/1. Conversely, their simultaneous disruption partially abrogates the requirement for WNT inactivation. These results suggest that human cardiac induction depends on multi-stage repression of alternate lineages, with implications for deriving expandable cardiac stem cells.
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    • "Inhibition of TNKS1/2 causes AXIN stabilization, leading to enhanced destruction of b-catenin and reduced Wnt signaling (Huang et al. 2009). Several small molecule TNKS1/2 inhibitors have been reported to cause inhibition of Wnt/ b-catenin signaling in cell lines as well as antitumor efficacy in selected colorectal cancer human xenograft mouse models (Chen et al. 2009; Huang et al. 2009; Waaler et al. 2011; Waaler et al. 2012; Lau et al. 2013). "
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    ABSTRACT: Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also critical for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in association with chronic inflammation of the submucosa. Therefore, the clinical utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.
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