CCA-1.1 Destabilizes MYC proteins to induce irreversible anti-proliferative effects in hepatocellular carcinoma.

N-Myc and c-Myc, as two major members of the MYC family proteins, independently contribute to hepatocellular carcinoma (HCC) by promoting proliferation, survival, and metabolic reprogramming. Overexpression of both proteins correlates with poor clinical outcomes, while intrinsic structural disorder hinder direct pharmacological targeting of MYC proteins. CCA-1.1 exhibits enhanced biological and physicochemical properties over its parent compound, curcumin, and demonstrates potent anti-cancer activity in various cancer types. We aim to investigate the anti-proliferative activity of CCA-1.1 through modulation of the MYC proteins and induction of cell cycle arrest and/or cell death mechanisms, including senescence, apoptosis, and autophagy. CCA-1.1 exhibited potent and irreversible anti-proliferative activity on Huh-6 cells by inhibiting EGFR kinase activity and its downstream signalling. CCA-1.1 also promoted G2/M arrest, induced apoptosis, and generated senescence. At the molecular level, CCA-1.1 downregulated N-Myc and c-Myc protein levels through the promotion of GSK3β activation and suppression of NCYM, a stabilizer protein of N-Myc. Furthermore, CCA-1.1 activated autophagy as a result of MYC protein destabilization. CCA-1.1 exerts a multi-faceted anti-cancer effect in MYCN-expressed HCC cells by inhibiting kinase signalling and destabilizing MYC proteins, leading to apoptosis, senescence, and autophagy. Molecular docking and molecular dynamic simulation revealed that CCA-1.1 interacted with both N-Myc and c-Myc. Our findings demonstrate CCA-1.1 as a distinctive anti-cancer candidate for HCC driven by MYC activation.