Future medicinal chemistry · 2026
Thiazolidin-based dual Aurora kinase inhibitors with potent anticancer activity.
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Elgammal Walid E, Elkady Hazem, Alsfouk Aisha A, Mahdy Hazem A, Husein Dalal Z, Amin Fatma G, Eissa Ibrahim H, Metwaly Ahmed M, Elkaeed Eslam B
Аннотация
AIMS: To design, synthesize, and evaluate novel thiazolidin derivatives as potential dual inhibitors of Aurora kinases for anticancer therapy.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Compound 11 is a promising dual Aurora kinase inhibitor with potent anticancer activity and high selectivity, representing a valuable lead for further development.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Compound 11 is a promising dual Aurora kinase inhibitor with potent anticancer activity and high selectivity, representing a valuable lead for further development.