Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer

By Baozhi Chen, Michael E. Dodge, Wei Tang, Jianming Lu, Zhiqiang Ma, C. Fan, Shuguang Wei, Wayne Hao, Jessica A. Kilgore, N. Williams and 4 more. Nature Chemical Biology, 2009

1,424 citations recorded by the source corpus.

SUMMARY 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 novel classes of small molecules that disrupt Wnt pathway responses - whereas one class inhibits the activity of Porcupine (Porcn), a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, suppressors of Wnt/β-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/β-catenin pathway response in vivo, and 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/41b63119ab8f24521541895223db0fd640b81556

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Citations in the corpus

Precise Regulation of Porcupine Activity Is Required for Physiological Wnt Signaling (2012, background): “Because of the importance ofWnt signaling in human disease, small molecule inhibitors of PORCN have been developed that inhibit Wnt signaling in cultured cells and in intestinal organoids (31, 32).”
Targeting Protein Lipidation in Disease (2012, background): “A series of small molecule inhibitors that target Porcn has been described and these compounds inhibit Wnt/ β-catenin pathway activation [62].”
Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, positive): “Despite containing a biaryl moiety that can insert deeply into the binding cavity of PORCN, IWP-L6 (a derivative of IWP-2) (Chen et al., 2009; Wang et al., 2013) has a much bulkier group at the lumenal side of the protein binding tunnel.”
An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine (2017, background): “Using cell-based Wnt signaling assays, small molecule inhibitors of PORCN have been identified, one of which (LGK974) has progressed to a clinical trial for treatment of Wnt-driven solid tumors (12, 13).”
The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge (2015, background): “Therefore, WNT-signalling inhibitors as well as small-molecule β-catenin inhibitors may serve as therapeutic approaches to treating CRC [60–62].”
Comprehensive Molecular Characterization of Human Colon and Rectal Cancer (2012, background): “Weinstein(39,40), University of California, Santa Cruz / Buck Institute – David Haussler(41,42), Christopher C.”
Wnt/β-catenin signaling in cancers and targeted therapies (2021, background): “In this study, the research group then verified the exclusive activity of inhibiting Wnt-related Porc function by using IWPs.299 IWP has three family members, IWP-1, −2, and -L6, all of which oppress Wnt/β-catenin signaling by competing for the active sites of Porc with Wntless.299 IWP-2 and IWP-L6 ”