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<p>Aurora kinases are a group of serine/threonine kinases essential for cell mitosis, comprising Aurora A, B, and C.&#xa0;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 <b>3-17a</b>, <b>3-17d</b> and <b>3-17&#xa0;k</b> especially inhibited Aurora B in the nanomolar range (IC<sub>50</sub> = 1.100, 1.518 and 0.8911&#xa0;nM, respectively), showing no significant inhibition of Aurora A. Notably, the most potent <b>3-17&#xa0;k</b> demonstrated the strongest antiproliferative activity against HGC27 (IC<sub>50</sub> = 2.05&#xa0;μM) and HT-29 (IC<sub>50</sub> = 2.07&#xa0;μM) cell lines, as well as Aurora B over-expression cells, including OVCAR8 (IC<sub>50</sub> = 3.02&#xa0;μM), T24 (IC<sub>50</sub> = 10.21&#xa0;μM), NCIH1299 (IC<sub>50</sub> = 7.32&#xa0;μM) and SW480 (IC<sub>50</sub> = 4.45&#xa0;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 <b>3-17&#xa0;k</b> and Aurora B (PDB: 5EYK), revealing favorable binding free energy (-33.34&#xa0;kcal·mol-1). Based on available data, compound <b>3-17&#xa0;k</b> warrants comprehensive investigation to evaluate its potential as an anticancer drug candidate.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年9月10日

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  • Baoxing Xie,
  • Miaomiao Shi,
  • Dan Tang,
  • Shan Yang,
  • Yan Zeng,
  • Lifei Nie,
  • Chao Niu

摘要

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.

Graphical abstract