Design and Synthesis of Novel Indolinone Aurora B Kinase Inhibitors Based on Fragment-Based Drug Discovery (FBDD)

Abstract 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 aurone scaffold hopping analog, and the indolinone-based Aurora B inhibitors library (3577 Mols) was performed by FBDD strategy. After pharmacophore model and molecular docking, the candidate molecules were identified and synthesized via Knoevenagel, Suzuki-Miyaura reaction. The compounds 3-17a, 3-17d and 3-17k especially inhibited Aurora B in the nanomolar range (IC₅₀= 1.100, 1.518 and 0.8911 nM, respectively), with a negligible activity against Aurora A. Notably, the most potent 3-17k demonstrated the strongest antiproliferative activity against HGC27 (IC₅₀ = 2.05 μM) and HT-29 (IC₅₀ = 2.07 μM) cell line, 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 low cytotoxicity in normal human cells (GES-1 and NCM460), representing >50-fold selectivity. Additionally, molecular dynamics simulation were conducted to explore the binding interactions between 3-17k and Aurora B (PDB: 5EYK), revealing favorable binding free energy (-33.34 kcal·mol-1). In summary, Compound 3-17k merits further investigation to discover a potential therapeutic candidate against cancer.