Design and synthesis of novel indolinone Aurora B kinase inhibitors based on fragment-based drug discovery (FBDD).

Aurora kinases are a group of serine/threonine kinases essential for cell mitosis, comprising Aurora A, B, and C. However, the Aurora B is overexpressed in multiple tumors and the aurone has been proved to exhibit potent inhibitory activity against Aurora B kinase by our group. The indolinone was considered as an aurone scaffold hopping analog, and the indolinone-based Aurora B inhibitor library (3577 molecules) was constructed by FBDD strategy. After pharmacophore model and molecular docking, the candidate molecules were identified, then synthesized via Suzuki-Miyaura and Knoevenagel reactions. The compounds 3-17a, 3-17d and 3-17 k especially inhibited Aurora B in the nanomolar range (IC₅₀ = 1.100, 1.518 and 0.8911 nM, respectively), showing no significant inhibition of Aurora A. Notably, the most potent 3-17 k demonstrated the strongest antiproliferative activity against HGC27 (IC₅₀ = 2.05 μM) and HT-29 (IC₅₀ = 2.07 μM) cell lines, as well as Aurora B over-expression cells, including OVCAR8 (IC₅₀ = 3.02 μM), T24 (IC₅₀ = 10.21 μM), NCIH1299 (IC₅₀ = 7.32 μM) and SW480 (IC₅₀ = 4.45 μM), while maintaining a lower cytotoxicity in normal human cells (GES-1 and NCM460). Additionally, molecular dynamics simulation were conducted to explore the binding interactions between 3-17 k and Aurora B (PDB: 5EYK), revealing favorable binding free energy (-33.34 kcal·mol-1). Based on available data, compound 3-17 k warrants comprehensive investigation to evaluate its potential as an anticancer drug candidate.