Discovery of N8: a novel IKKε inhibitor with potent anticancer activity via cytotoxicity, migration suppression, and autophagy modulation

The serine/threonine kinase IKKε is overexpressed or activated in various cancers, making it a promising therapeutic target. Through a large-scale virtual screening of over 12 million compounds, we identified N8 as a novel IKKε inhibitor, selected for its favourable docking score and drug-likeness profile. The inhibitory activity of N8 on IKKε was validated in vitro across several cancer cell lines, including HCT116 (colorectal), HepG2 (liver), T24 (bladder), MDA-MB-231 (breast), A549 (lung), and HeLa (cervical). N8 demonstrated significant reductions in cell viability, colony formation, and migration, particularly in HCT116 colorectal cancer cells, where it exhibited superior efficacy compared to established IKKε inhibitors. Mechanistically, N8's anticancer activity appears to be mediated through modulation of autophagy rather than apoptosis.