Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer,Chemical Biology & Drug Design

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Design strategies, SAR, and mechanistic insight of Aurora kinase inhibitors in cancer
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2021-05-02 , DOI: 10.1111/cbdd.13850
Kaksha Sankhe ₁ , Arati Prabhu ₂ , Tabassum Khan ₂

Affiliation

Aurora kinases (AURKs) are serine/threonine protein kinases that play a critical role during cell proliferation. Three isoforms of AURKs reported in mammals include AURKA, AURKB, AURKC, and all share a similar C-terminal catalytic domain with differences in their subcellular location, substrate specificity, and function. Recent research reports indicate an elevated expression of these kinases in several cancer types highlighting their role as oncogenes in tumorigenesis. Inhibition of AURKs is an attractive strategy to design potent inhibitors modulating this target. The last few years have witnessed immense research in the development of AURK inhibitors with few FDA approvals. The current clinical therapeutic regime in cancer is associated with severe side-effects and emerging resistance to existing drugs. This has been the key driver of research initiatives toward designing more potent drugs that can potentially circumvent the emerging resistance. This review is a comprehensive summary of recent research on AURK inhibitors and presents the development of scaffolds, their synthetic schemes, structure–activity relationships, biological activity, and enzyme inhibition potential. We hope to provide the reader with an array of scaffolds that can be selected for further research work and mechanistic studies in the development of new AURK inhibitors.

中文翻译：

极光激酶抑制剂在癌症中的设计策略、SAR 和机制洞察

极光激酶 (AURK) 是丝氨酸/苏氨酸蛋白激酶，在细胞增殖过程中起关键作用。哺乳动物中报道的三种 AURK 亚型包括 AURKA、AURKB、AURKC，它们都具有相似的 C 端催化结构域，但它们的亚细胞位置、底物特异性和功能不同。最近的研究报告表明这些激酶在几种癌症类型中的表达升高，突出了它们作为致癌基因在肿瘤发生中的作用。抑制 AURK 是设计调节该目标的有效抑制剂的有吸引力的策略。过去几年见证了 AURK 抑制剂开发方面的大量研究，但几乎没有获得 FDA 的批准。当前的癌症临床治疗方案与严重的副作用和对现有药物的新出现的耐药性有关。这一直是设计更有效药物的研究计划的关键驱动力，这些药物可能会规避新出现的耐药性。这篇综述是对 AURK 抑制剂最近研究的全面总结，并介绍了支架的发展、它们的合成方案、结构-活性关系、生物活性和酶抑制潜力。我们希望为读者提供一系列支架，可以选择这些支架用于新 AURK 抑制剂开发的进一步研究工作和机理研究。和酶抑制潜力。我们希望为读者提供一系列支架，可以选择这些支架用于新 AURK 抑制剂开发的进一步研究工作和机理研究。和酶抑制潜力。我们希望为读者提供一系列支架，可以选择这些支架用于新 AURK 抑制剂开发的进一步研究工作和机理研究。

更新日期：2021-06-21

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