Discovery of novel SIRT2 inhibitors with anti-NSCLC activity through multi-virtual screening and biological evaluation

Screening yielded 20 candidate SIRT2 inhibitors. Compound 7 was the most potent inhibitor. Mechanistically, Compound 7 dose-dependently increased acetylation of α-tubulin (a key SIRT2 substrate) in H441 cells, confirming direct target modulation. Cellular assays demonstrated that Compound 7 significantly inhibited H441 cell proliferation, induced apoptosis, and suppressed migration and invasion. Critically, Compound 7 also markedly inhibited tumor growth in H441 xenograft mouse models. These integrated results, spanning virtual screening to in vivo validation, identify Compound 7 as a promising lead compound. The study establishes a solid foundation for developing novel SIRT2 inhibitors as both chemical probes and potential therapeutics for SIRT2-driven NSCLC.