The canonical Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as differentiation and migration. Deregulation of components involved in Wnt/β-catenin signaling has been implicated in a wide spectrum of diseases including several cancers and degenerative diseases. Recent data suggests pre-cancerous cells overexpress the protein β-catenin when they become cancerous cells by Wnt stabilization and nuclear localization, ultimately activating the expression of β-catenin mediated genes downstream. However, in the absence of Wnt ligand stimulation, several proteins participate in a multiprotein “destruction complex” that targets the proto-oncogene β-catenin for ubiquitin-mediated proteolysis, resulting in the inhibition of downstream gene expression. To inhibit β-catenin accumulation, we designed and synthesized a library of novel small molecules that can inhibit Wnt signaling in various cancers by blocking specific protein–protein interactions or the activity of specific enzymes. We hypothesize that small molecules that reduced β-catenin levels can potentially function as anti-cancer drugs. To test this hypothesis, various small molecules with modified structures were synthesized and purified. To assess and quantify cell proliferation, the fluorescence-based CyQUANT assay was used to measure DNA content. Total β-catenin levels that are associated with raised nuclear and cytosolic pools were determined by immunocytochemistry. Our recent findings show that several small molecules contain a specific moiety that exhibit higher inhibitory activities in cell-based assays than known inhibitors and show promising results to reduce β-catenin levels. Recent studies have also indicated that a specific kinase exerting tumor suppressor function has been hampered by the lack of selective inhibitors. A next generation of drug compounds will focus on molecules with similar functionalities but greater rigidity to target this protein to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway. Docking studies and cell-based assays will compare the results of the original drugs to those of the new series to determine the best method to increase phosphorylation of β-catenin, thereby generating more potent anti-cancer drugs.

Structure-based discovery of novel small molecule Wnt/β-catenin signaling inhibitors

253rd National Meeting (2017)

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