Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Biomedical Science and Technology, UST KIST School, Seoul 02792, Republic of Korea.
Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
Bioorg Med Chem. 2024 Mar 15;102:117658. doi: 10.1016/j.bmc.2024.117658. Epub 2024 Feb 27.
Aurora kinases (AurkA/B/C) regulate the assembly of bipolar mitotic spindles and the fidelity of chromosome segregation during mitosis, and are attractive therapeutic targets for cancers. Numerous ATP-competitive AurkA inhibitors have been developed as potential anti-cancer agents. Recently, a few allosteric inhibitors have been reported that bind to the allosteric Y-pocket within AurkA kinase domain and disrupt the interaction between AurkA and its activator TPX2. Herein we report a novel allosteric AurkA inhibitor (6h) of N-benzylbenzamide backbone. Compound 6h suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 6h against AurkA (IC = 6.50 μM) was comparable to that of the most potent allosteric AurkA inhibitor AurkinA. Docking analysis against the Y-pocket revealed important pharmacophores and interactions that were coherent with structure-activity relationship. In addition, 6h suppressed DNA replication in G1-S phase, which is a feature of allosteric inhibition of AurA. Our current study may provide a useful insight in designing potent allosteric AurkA inhibitors.
极光激酶（AurkA/B/C）调节有丝分裂中双极纺锤体的组装和染色体分离的保真度，是癌症有吸引力的治疗靶点。已经开发了许多 ATP 竞争性 AurkA 抑制剂作为潜在的抗癌药物。最近，已经报道了一些别构抑制剂，它们结合到 AurkA 激酶结构域中的别构 Y 口袋中，并破坏 AurkA 与其激活剂 TPX2 之间的相互作用。在此，我们报告了一种新型的 N-苄基苯甲酰胺骨架的别构 AurkA 抑制剂（6h）。化合物 6h 抑制了 AurkA 的催化活性和非催化功能。6h 对 AurkA 的抑制活性（IC=6.50μM）与最有效的别构 AurkA 抑制剂 AurkinA 相当。针对 Y 口袋的对接分析揭示了与结构活性关系一致的重要药效团和相互作用。此外，6h 抑制了 G1-S 期的 DNA 复制，这是 AurA 别构抑制的一个特征。我们目前的研究可能为设计有效的别构 AurkA 抑制剂提供有用的见解。
