Cytotoxic effects of Methoxy-substituted Chalcones on glioblastoma stem cells: Computational target prediction and therapeutic insights

The prognosis for patients diagnosed with glioblastoma remains dismal with an average survival of about 15 months. Recently, it has been shown that glioblastoma stem-like cells (GSCs) drive tumor progression and are responsible for tumor regrowth following treatment; therefore, successful elimination of this cell population is necessary for disease eradication. Methoxy substituted chalcones have demonstrated anti-cancer effects with diverse molecular mechanisms. In this study, we synthesized 24 methoxy containing compounds, including 5 novel compounds, and tested their cytotoxicity toward 3 GSC lines and 2 non-tumor cell lines. We identified 13 compounds demonstrating an average GSC IC₅₀ value below 10 μM, many of which were less toxic to the non-cancer cell lines. In silico reverse screening identified probable targets for 7 out of the 13 active compounds. Some targets have been well-investigated such as the epidermal growth factor receptor; however, others such as 17-beta hydroxysteroid dehydrogenase type 3 warrant further study.