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 () of -benzylbenzamide backbone. Compound suppressed the both catalytic activity and non-catalytic functions of AurkA. The inhibitory activity of 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, 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.

中文翻译：

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发现基于 N-苄基苯甲酰胺的 Aurora 激酶 A 变构抑制剂

极光激酶 (AurkA/B/C) 调节双极有丝分裂纺锤体的组装和有丝分裂过程中染色体分离的保真度，是有吸引力的癌症治疗靶点。许多 ATP 竞争性 AurkA 抑制剂已被开发为潜在的抗癌药物。最近，据报道，一些变构抑制剂可与 AurkA 激酶结构域内的变构 Y 袋结合，并破坏 AurkA 与其激活剂 TPX2 之间的相互作用。在此，我们报道了一种新型的β-苄基苯甲酰胺主链变构AurkA抑制剂()。化合物抑制AurkA的催化活性和非催化功能。针对 AurkA 的抑制活性 (IC = 6.50 μM) 与最有效的 AurkA 变构抑制剂 AurkinA 相当。针对 Y 型口袋的对接分析揭示了与结构-活性关系一致的重要药效基团和相互作用。此外，抑制 G1-S 期的 DNA 复制，这是 AurA 变构抑制的一个特点。我们目前的研究可能为设计有效的变构 AurkA 抑制剂提供有用的见解。