Xie Baoxing, Shi Miaomiao, Tang Dan, Yang Shan, Zeng Yan, Nie Lifei, Niu Chao
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, Xinjiang, China.
University of Chinese Academy of Science, Beijing, 10004, China.
Mol Divers. 2025 Sep 10. doi: 10.1007/s11030-025-11353-w.
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 (IC = 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 (IC = 2.05 μM) and HT-29 (IC = 2.07 μM) cell lines, as well as Aurora B over-expression cells, including OVCAR8 (IC = 3.02 μM), T24 (IC = 10.21 μM), NCIH1299 (IC = 7.32 μM) and SW480 (IC = 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.
极光激酶是一组对细胞有丝分裂至关重要的丝氨酸/苏氨酸激酶，包括极光激酶A、B和C。然而，极光激酶B在多种肿瘤中过表达，并且我们团队已证明奥洛酮对极光激酶B具有强大的抑制活性。吲哚酮被认为是一种奥洛酮骨架跳跃类似物，基于吲哚酮的极光激酶B抑制剂库（3577个分子）通过片段药物发现（FBDD）策略构建。经过药效团模型和分子对接后，确定了候选分子，然后通过铃木-宫浦反应和克诺文纳格尔反应进行合成。化合物3-17a、3-17d和3-17k尤其在纳摩尔范围内抑制极光激酶B（IC分别为1.100、1.518和0.8911 nM），对极光激酶A无明显抑制作用。值得注意的是，最有效的3-17k对HGC27（IC为2.05 μM）和HT-29（IC为2.07 μM）细胞系以及极光激酶B过表达细胞，包括OVCAR8（IC为3.02 μM）、T24（IC为10.21 μM）、NCIH1299（IC为7.32 μM）和SW480（IC为4.45 μM）表现出最强的抗增殖活性，同时在正常人类细胞（GES-1和NCM460）中保持较低的细胞毒性。此外，进行了分子动力学模拟以探索3-17k与极光激酶B（PDB：5EYK）之间的结合相互作用，揭示了有利的结合自由能（-33.34 kcal·mol-1）。基于现有数据，化合物3-17k值得进行全面研究以评估其作为抗癌药物候选物的潜力。
