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

  • J Enzyme Inhib Med Chem. 2026 Dec;41(1):2607808. doi: 10.1080/14756366.2025.2607808.
Wei Ye  1  2 ,  Siying Zheng  1 ,  Hongmei Xie  1 ,  Xinrui Zhou  1  2 ,  Jiapeng Xu  1  2 ,  Qiting Luo  1  2 ,  Yuanyuan Huang  1 ,  Jieyu Li  1 ,  Jiayi Diao  1  2 ,  Xinyi Luo  1  2 ,  Qinchang Zhu  1 ,  Ge Liu  1
Affiliations
  • 1. College of Pharmacy, Shenzhen Technology University, Shenzhen, China.
  • 2. School of Pharmaceutical Sciences, Shenzhen University, Shenzhen, China.
PMID: 41492864 DOI: 10.1080/14756366.2025.2607808
Abstract

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.

Keywords
IKKε; Targeted cancer therapy; autophagy; inhibitor; virtual screening.
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