Aurora kinases are essential enzymes for the control of cell cycle. The specific role of aurora kinase A (AURKA) is the regulation of spindle assembly and stability by promoting centrosome maturation and separation. Because AURKA is an essential protein for the normal occurrence of the cycle, mutations and deregulations in the activities of this protein are associated with several cancers. The kinase activity of AURKA is controlled by autocatalytic phosphorylation, which is facilitated after binding to a regulator protein, the Target Protein for Xenopuskinesin-like protein 2 (TPX2).

Scope of review

This review highlights the physiological and pathophysiological properties of AURKA, the structure of the AURKA/TPX2 complex and the main structural features that can be explored for the design of selective AURKA inhibitors.

Major conclusions

The design of selective AURKA inhibitors remains as a challenge as most of the currently available inhibitors target only the ATP binding cleft and are nonselective among kinases. However, by exploring the inactive form of the kinase, researchers get access to an adjacent hydrophobic pocket, allowing the design of more selective inhibitors. Additionally, the possibility of designing potent allosteric AURKA inhibitors look very promising from the clinical perspective, since it tends to yield the most selective class of compounds.

General significance

Herein we detailed the binding modes of the most selective AURKA inhibitors currently reported. We believe this will aid researchers in defining the structural patterns necessary for selective AURKA inhibition, guiding the design of more potent compounds to be therapeutically explored in cancer patients.

中文翻译：

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在癌症化疗中设计Aurora激酶A酶的变构抑制剂的结构基础。

极光激酶是控制细胞周期的重要酶。极光激酶A（AURKA）的特定作用是通过促进中心体成熟和分离来调节纺锤体组装和稳定性。由于AURKA是周期正常发生所必需的蛋白质，因此该蛋白质活性的突变和失调与多种癌症有关。AURKA的激酶活性受自身催化磷酸化的控制，该磷酸化与调节蛋白结合后即为异滑膜素样蛋白2（TPX2）的靶蛋白而得以促进。

审查范围

这篇综述重点介绍了AURKA的生理和病理生理特性，AURKA / TPX2复合物的结构以及可用于设计选择性AURKA抑制剂的主要结构特征。

主要结论

选择性AURKA抑制剂的设计仍然是一个挑战，因为大多数当前可用的抑制剂仅靶向ATP结合裂，并且在激酶之间是非选择性的。但是，通过探索激酶的失活形式，研究人员可以进入相邻的疏水口袋，从而设计出更具选择性的抑制剂。另外，从临床角度来看，设计有效的变构AURKA抑制剂的可能性看起来非常有前途，因为它倾向于产生最具选择性的一类化合物。

一般意义

本文中，我们详细介绍了目前报道的最具选择性的AURKA抑制剂的结合模式。我们相信这将有助于研究人员确定选择性抑制AURKA所必需的结构模式，指导在癌症患者中进行治疗性探索的更有效化合物的设计。