Sankhe Kaksha, Prabhu Arati, Khan Tabassum
Department of Pharmaceutical Chemistry, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
Department of Pharmaceutical Chemistry and Quality Assurance, Bhanuben Nanavati College of Pharmacy, Mumbai, India.
Chem Biol Drug Des. 2021 Jul;98(1):73-93. doi: 10.1111/cbdd.13850. Epub 2021 May 15.
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.
极光激酶（AURKs）是丝氨酸/苏氨酸蛋白激酶，在细胞增殖过程中起关键作用。在哺乳动物中报道的AURKs的三种同工型包括AURKA、AURKB、AURKC，它们都共享一个相似的C端催化结构域，但其亚细胞定位、底物特异性和功能存在差异。最近的研究报告表明，这些激酶在几种癌症类型中表达升高，突出了它们在肿瘤发生中作为癌基因的作用。抑制AURKs是设计强效抑制剂调节该靶点的一种有吸引力的策略。在过去几年中，对AURK抑制剂的开发进行了大量研究，但只有少数获得了美国食品药品监督管理局（FDA）的批准。目前癌症的临床治疗方案伴随着严重的副作用和对现有药物的新出现的耐药性。这一直是设计更有效药物以潜在规避新出现的耐药性的研究计划的关键驱动力。这篇综述全面总结了最近关于AURK抑制剂的研究，并介绍了骨架的开发、它们的合成方案、构效关系、生物活性和酶抑制潜力。我们希望为读者提供一系列骨架，可用于新AURK抑制剂开发中的进一步研究工作和机制研究。
