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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The serine/threonine kinase IKKε is frequently overexpressed or activated in various cancers.
• IKKε represents a promising therapeutic target for cancer treatment.

Purpose of the Study:

• To identify novel inhibitors of IKKε through large-scale virtual screening.
• To evaluate the anticancer efficacy and mechanism of action of the identified inhibitor N8.

Main Methods:

• Large-scale virtual screening of over 12 million compounds to identify potential IKKε inhibitors.
• In vitro validation of N8's inhibitory activity across multiple human cancer cell lines (HCT116, HepG2, T24, MDA-MB-231, A549, HeLa).
• Assessment of N8's effects on cell viability, colony formation, migration, and underlying molecular mechanisms (autophagy vs. apoptosis).

Main Results:

• N8 was identified as a novel IKKε inhibitor with favorable docking score and drug-likeness.
• N8 demonstrated significant inhibition of cell viability, colony formation, and migration in tested cancer cell lines.
• N8 showed superior efficacy in HCT116 colorectal cancer cells compared to existing IKKε inhibitors.
• The anticancer effects of N8 were primarily mediated through modulation of autophagy, not apoptosis.

Conclusions:

• N8 is a potent novel inhibitor of IKKε with significant anticancer activity, particularly in colorectal cancer.
• N8's mechanism of action involves the modulation of autophagy, offering a distinct therapeutic strategy.
• N8 warrants further investigation as a potential targeted therapy for cancers with IKKε overexpression.