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Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: A high-throughput screening approach

Dept. of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 08/2010; 299(2):G293-300. DOI: 10.1152/ajpgi.00005.2010
Source: PubMed

ABSTRACT Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory's strategy for identifying novel Wnt signaling antagonists using high-throughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.

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    • "Although these agents efficiently inhibit Wnt signaling in normal cells and some APC-mutated colon cancer cells, they may not be effective in cells containing b-catenin mutations [21]. Despite in the last years many advances have been achieved in that field, the majority of patients relapses and the survival with metastatic disease remains approximately two years, indicating the need for new therapies that may produce dramatic improvements [22]. As just noted, high-throughput screening of synthetic compounds libraries was used to identify several Wnt inhibitors [20] [23] [24], as well as agonists [25] [26]. "
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    ABSTRACT: Wnt/β-catenin signaling plays an important role in the regulation of embryonic development and tumorigenesis. Since its deregulation results in severe human diseases, especially cancer, the Wnt signaling pathway constitutes a promising platform for pharmacological targeting of cancer. In this study we synthesized a series of imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyridines and identified some derivatives that were able to inhibit the Wnt/β-catenin signaling pathway in a luciferase reporter assay and cell proliferation in selected cancer cell lines, endowed with APC or β-catenin gene mutations. The most active compounds significantly downregulate the expression of Wnt target genes such as c-myc and cyclin D1. Further studies indicated that these compounds function independently of GSK-3β activity. More importantly, in vivo experiments, carried out on a Wnt-reporter zebrafish model indicate, in particular for compounds 4c and 4i as the most active compounds, an activity comparable to that of the reference compound IWR1, suggesting their potential use not only as small molecule inhibitors of the Wnt/β-catenin signal in Wnt driven cancers, but also in other Wnt-related diseases.
    European Journal of Medicinal Chemistry 06/2014; 83C:45-56. DOI:10.1016/j.ejmech.2014.05.071 · 3.43 Impact Factor
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    • "The IWP compounds share an identical core chemical structure and target the palmitoyltransferase PPN (10,11). As the majority of currently used Wnt pathway-targeting strategies have focused on Wnt-receiving cells (12,13), the potential use of IWP may provide new insights into the abrogation of aberrant Wnt signaling pathway activity in Wnt-producing cells and cancer therapy. "
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    ABSTRACT: Similarly to the Wnt protein palmitoyltransferase, porcupine (PPN) is essential to the activation of the Wnt/β-catenin signaling pathway. However, little is known about the role of PPN activity in human gastric cancer, one of the most common causes of cancer-related mortality. Real-time quantitative PCR was used to detect the expression levels of PPN in paired gastric cancer tissues. Cell proliferation, migration and invasion assays were performed following treatment using a newly developed small molecule PPN inhibitor (inhibitors of Wnt production, IWP-2) in the gastric cancer MKN28 cell line. Expression of downstream target genes and transcriptional activity of the Wnt/β-catenin signaling pathway were examined following IWP-2 treatment in MKN28. We identified that PPN was overexpressed in human gastric cancer tissue samples and cell lines. Following treatment of the gastric cancer cell line MKN28 with IWP-2, we detected that IWP-2 decreased MKN28 cell proliferation, migration and invasion, and elevated caspase 3/7 activity. Further analysis demonstrated that IWP-2 downregulated the transcriptional activity of the Wnt/β-catenin signaling pathway and downregulated the expression levels of downstream Wnt/β-catenin target genes in MKN28 cells. As current Wnt pathway-targeting strategies used for anticancer therapy have mainly focused on Wnt-receiving cells, our data shed light on the potential use of Wnt palmitoyltransferase PPN inhibitors to abrogate Wnt production in Wnt-producing cells, thus providing a potential therapeutic option for gastric cancer.
    Oncology letters 05/2013; 5(5):1719-1723. DOI:10.3892/ol.2013.1256 · 0.99 Impact Factor
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    • "Activation of this pathway is higher in nearly all the cancer samples compared to the normal samples. Wnt inhibitors are the subject of intense investigation in pharmaceutical and academic research [71-73]. These results suggest they will have an indication in gastric cancer as well as many other cancers. "
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    ABSTRACT: Globally, gastric cancer is the second most common cause of cancer-related death, with the majority of the health burden borne by economically less-developed countries. Here, we report a genetic characterization of 50 gastric adenocarcinoma samples, using affymetrix SNP arrays and Illumina mRNA expression arrays as well as Illumina sequencing of the coding regions of 384 genes belonging to various pathways known to be altered in other cancers. Genetic alterations were observed in the WNT, Hedgehog, cell cycle, DNA damage and epithelial-to-mesenchymal-transition pathways. The data suggests targeted therapies approved or in clinical development for gastric carcinoma would be of benefit to ~22% of the patients studied. In addition, the novel mutations detected here, are likely to influence clinical response and suggest new targets for drug discovery.
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