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

Identify novel SIRT2 inhibitors for treating non-small cell lung cancer (NSCLC). A hierarchical virtual screening strategy (combining ligand- and receptor-based pharmacophore modeling with molecular docking) screened a 203,415-compound library. Identified candidates were tested for SIRT2 inhibition using a fluorogenic assay (AcIQF). Anti-tumor effects (proliferation, apoptosis, migration, invasion) were assessed in high-SIRT2-expressing H441 NSCLC cells. Target engagement was confirmed via Western blot (WB) analysis of SIRT2 substrate acetylation. In vivo efficacy was evaluated using H441 xenograft models in nude mice. 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.