A synthetic benzoxazine dimer derivative targets c-Myc to inhibit colorectal cancer progression.

The c-Myc protein is a well-known oncoprotein that plays a crucial role in regulating cell growth, proliferation, and differentiation. The overexpression or dysregulation of c-Myc is commonly associated with tumorigenesis in several cancers, including colorectal cancer (CRC). c-Myc forms a heterodimer with its partner MAX to activate the expression of various genes. Here, we synthesized a novel c-Myc-targeting small molecule, 2,2'-((cyclohexylazanedyl)bis(methylene))bis(4-ethylphenol), or ECD, and demonstrate ECD's anticancer activity via interference with the c-Myc/MAX dimer to promote c-Myc degradation in CRC cells in vitro, in silico, and in vivo. This study revealed the activity of ECD toward CRC cells as a c-Myc inhibitor. Computer-aided analysis revealed that the effect of ECD was mediated through disturbance of the c-Myc/MAX complex. Moreover, ECD exhibited cytotoxic activity by inducing DNA damage, leading to apoptotic cell death. This DNA damage-inducing property was also confirmed by whole-proteome profiling of HT29 cells after ECD treatment. In the chick embryo chorioallantoic membrane (CAM) xenograft assay, we demonstrated a remarkable inhibition of the tumorigenic activity upon ECD exposure. In summary, we identified ECD as a novel potent compound targeting the oncoprotein c-Myc that may offer new opportunities for CRC treatment.