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

Area of Science:

• Oncology
• Epigenetics
• Medicinal Chemistry

Background:

• Colon cancer is a leading cause of cancer mortality globally, driven by genetic and epigenetic alterations.
• Histone methyltransferases (HMTs) play a crucial role in epigenetic regulation and tumorigenesis.
• Existing HMT inhibitors have limited clinical success, necessitating the development of novel therapeutic agents.

Purpose of the Study:

• To design and synthesize novel small molecular compounds as potential HMT inhibitors.
• To evaluate the anti-cancer efficacy of these compounds, particularly against colon cancer cell lines.
• To investigate the mechanism of action and safety profile of promising drug candidates.

Main Methods:

• Synthesis of small molecular compounds, including 1-benzylpiperidin-4-amine derivatives.
• Assessment of anti-proliferative effects in various cancer cell lines.
• Evaluation of HMT activity, cell migration, epithelial-mesenchymal transition (EMT) markers, apoptosis, and cell cycle regulation.
• In vitro drug safety assessment using non-cancerous human cell lines and in vivo zebrafish embryotoxicity model.

Main Results:

• Two compounds, DHT-07343 and DHT-07171, demonstrated significant anti-cancer potential, especially in colon cancer cells.
• These compounds suppressed methyltransferase activity, potentially by regulating NSD1 and NSD2.
• DHT-07343 and DHT-07171 inhibited cancer cell migration, modulated EMT markers, induced apoptosis, and regulated the cell cycle.

Conclusions:

• DHT-07343 and DHT-07171 are identified as promising HMT inhibitors with significant anti-cancer activities.
• These compounds offer a potential therapeutic strategy for colon cancer by targeting cell proliferation and migration.
• Further investigation into the safety and efficacy of DHT-07343 and DHT-07171 is warranted for clinical development.