Targeting epithelial-mesenchymal transition and apoptosis: novel histone methyltransferase inhibitors for colon cancer suppression

Colon cancer is one of the major causes of cancer-related death worldwide and is considered a consequence of the accumulation of genetic and epigenetic changes in normal cells. Among epigenetic modifications, the critical involvement of histone methyltransferase (HMT) in epigenetic alterations and tumorigenesis has been widely reported. Targeting HMTs as an anti-cancer strategy has attracted considerable attention; however, limited HMT inhibitors have achieved success in the field of clinical oncology.In this study, we aimed to design and synthesize small molecular compounds as potential HMT inhibitors for cancer therapy, and to investigate their biological impacts on cancer cell lines. We examined the anti-proliferative effect of potential HMT inhibitors in multiple cancer cell lines. Among all candidates, two 1-benzylpiperidin-4-amine derivatives, DHT-07343 and DHT-07171, exhibited the most significant anti-cancer potential, especially in colon cancer cells. These two compounds could suppress methyltransferase activity, likely via regulating nuclear receptor-binding SET domain protein 1 (NSD1) and NSD2. In addition, these two compounds were able to inhibit cancer cell migration and regulate epithelial-mesenchymal transition (EMT) markers. Treatment of these two compounds led to apoptosis induction as well as cell cycle regulation. Finally, non-cancerous human cell lines and the zebrafish embryotoxicity model were utilized for the evaluation of the drug safety of DHT-07343 and DHT-07171.In conclusion, our study demonstrated that DHT-07343 and DHT-07171 could be promising HMT inhibitors that exhibit anti-cancer activities by suppressing cell proliferation and migration, providing a potential strategy for colon cancer therapy.