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Designer Small Molecule Compounds to Regulate Β-catenin for Anti-cancer Activity
The Wnt Signaling pathway has been implicated in stem cell maintenance and incidence of various types of cancer due to the presence of β-catenin, a transcriptional coactivator. It binds to TCF/LEF family proteins and activates the transcription of target genes such as c-myc or cyclin D1 which are necessary for cell division. This project began by synthesizing small molecules to promote the accumulation of β-catenin to maintain stem cell pluripotency. However, TOPFlash, a method that indirectly measures β-catenin, suggested that some compounds significantly decreased β-catenin levels. Because Wnt signaling (elevated levels of β-catenin) is also implicated in cancer, the project shifted towards synthesizing compounds with similar scaffolds to lower β-catenin levels. Goals of the project were to identify important functional groups by probing physical and chemical characteristics such as sterics, electronic effects, and polarity, and account for cost and ease of synthesis for a more practical application. Cell proliferation assay data shows an interesting trend towards bulky alkyl groups and their observable decrease in cell growth compared to more electron withdrawing groups or even their shorter or longer chained counterparts. Compounds that performed well in their initial cell proliferation screenings were tested with immunocytochemistry assays to visualize β-catenin accumulation and western blots to quantify the concentration of β-catenin via intensity and thickness of the band, potentially implicating the role of the compounds and their disruption of Wnt signaling.
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