Thiazolidin-based dual Aurora kinase inhibitors with potent anticancer activity

Résumé fourni par la source

To design, synthesize, and evaluate novel thiazolidin derivatives as potential dual inhibitors of Aurora kinases for anticancer therapy. A series of thiazolidin derivatives was designed and evaluated for in vitro cytotoxic activity against HCT-116, MCF-7, HepG-2, and HeLa cancer cell lines. The most active compound was further investigated using kinase assays, cell cycle analysis, wound healing migration assays, and molecular dynamics simulations combined with Molecular Mechanics–Generalized Born Surface Area (MM-GBSA) analysis. Compound 11 exhibited potent antiproliferative activity with IC50 values of 0.32 ± 0.094 µM (HCT-116) and 0.15 ± 0.03 µM (MCF-7), with high selectivity indices of 242.5 and 517.0, respectively, compared with Vero cells (IC50 = 77.6 ± 1.8 µM). At the enzymatic level, compound 11 inhibited Aurora A and Aurora B with IC50 values of 0.23 and 0.91 µM, respectively, compared with Danusertib (0.13 and 0.25 µM), indicating comparable Aurora A inhibition. Compound 11 significantly reduced Aurora kinase levels, induced G2/M arrest, and triggered apoptosis. Molecular dynamics and MM-GBSA confirmed stable binding interactions. Compound 11 is a promising dual Aurora kinase inhibitor with potent anticancer activity and high selectivity, representing a valuable lead for further development.

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