A novel 1,2,4-triazole derivative inhibits epithelial-mesenchymal transition in metastatic colorectal cancer via β-catenin suppression

1,2,4-Triazole derivatives have emerged as a significant class of compounds with diverse biological activities, notably their Anticancer properties. This therapeutic utility lies in their molecular flexibility and their capacity to interact with key Enzymes implicated in oncogenesis. However, their role in inhibiting tumor cell metastasis is not fully investigated. Hence, we assessed the ability of a series of 5-heptadecyl-4H-1,2,4-triazole incorporated N-substituted indoles, which we previously developed, to suppress the migration of metastatic colorectal Cancer. To achieve that, we analyzed the mechanism underlying the antitumor effect of compound 10d, which demonstrated the highest antitumor activity among the synthesized 1,2,4-triazole/indole hybrids. Furthermore, we investigated the potential of compound 10d to inhibit epithelial-mesenchymal transition (EMT) in colorectal Cancer cells. Our findings showed that compound 10d exerts its antitumor action by inducing both Apoptosis and cell cycle arrest at S-phase. Moreover, 10d inhibited the migration and invasion of colorectal Cancer cells in vitro, in addition to EMT inhibition. This inhibition was attributed to its capacity to suppress the transcription of β-catenin and vimentin, which are key markers of EMT. Additionally, 10d significantly inhibited β-catenin at the protein level. Collectively, our findings highlight the promising potential of 10d as a novel therapeutic agent for reducing cell migration and invasion, thereby inhibiting colorectal Cancer metastasis. Molecular docking study supported the results for compound 10d. Where 10d showed strong binding affinity to a human β-catenin complex (PDB ID: 2GL7) (-6.5 kcal/mol) via hydrogen bonds and hydrophobic interactions, along with specific drug-likeness properties, including favorable oral absorption, moderate solubility, and a safer toxicity profile, despite some metabolic limitations.

1,2,4-Triazole; Colorectal cancer cell; Epithelial-mesenchymal transition; Indole; Molecular docking; β-catenin.