Methoxy and Ketone Substitutions of Resveratrol Enhance Its Anticancer Activity by Increasing MEK and ERK Binding Affinity in Colorectal Cancer Cells

Background/Aim: Colorectal cancer remains a major cause of cancer mortality, driven by recurrence, metastasis, and resistance to therapy. Resveratrol (Res) has notable anticancer properties, yet its clinical utility is limited by poor stability and bioavailability. This study investigated the anticancer activity of SM-23, a Res derivative containing methoxy and ketone substitutions designed to enhance target binding and potency. Materials and Methods: The IC₅₀ value of SM-23, in HCT116 colon cancer cells was evaluated using the MTT viability assay. In addition, cell proliferation was assessed through a colony formation assay, while apoptosis-related proteins were analyzed using western blotting. Molecular docking was performed to compare the binding affinities of SM-23 and Res toward key kinases in the PI3K/AKT and MEK/ERK pathways. Results: Molecular docking analysis showed that SM-23 exhibited higher binding energies toward MEK1 and ERK compared to Res. The binding affinity of SM-23 was enhanced for AKT, ERK, and MEK1, whereas no improvement was observed for PI3K relative to the parent compound Res. According to our results, SM-23 treatment markedly reduced MEK and ERK phosphorylation in HCT116 cells. At 20 μM and 30 μM, SM-23 decreased pMEK levels by approximately 2.5-fold and 3-fold, respectively, showing a stronger effect than Res. Furthermore, SM-23 at 30 μM significantly lowered the p-ERK/ERK ratio by about 5-fold compared to control cells, exceeding the reduction caused by Res. Conclusion: SM-23 enhances MEK/ERK pathway inhibition through improved kinase binding affinity and demonstrates potent antiproliferative activity in colorectal cancer cells. These findings identify SM-23 as a promising MEK/ERK-targeted candidate for further therapeutic development.