Recent advancements in mechanistic research, therapeutic potential, and structure-activity relationships of aurora kinase inhibitors in cancer therapies.

Aurora kinases (AURKs)-a family of serine/threonine protein kinases consisting of AURK-A, AURK-B, and AURK-C, are critical regulators of chromosomal segregation, centrosome maturation, and cytokinesis during the cell cycle. Each kinase is activated via phosphorylation at unique threonine residues: Thr288 (AURK-A), Thr232 (AURK-B), and Thr195 (AURK-C). Activation of AURK-A and AURK-B through phosphorylation triggers a series of downstream signaling pathways, including RalA, NF-κB, p53, PLK1, BRCA1/BRCA2, H2AX, and Kif2C, as well as multiple transmembrane kinase receptors. Dysregulation of these pathways has been implicated in cancer development and progression, positioning AURKs as pivotal targets for anticancer drug research. Inhibition of AURKs has demonstrated significant efficacy in tumor growth suppression and induction of cancer cell death, thereby focusing recent research on the development of potent AURK inhibitors. This review provides an in-depth exploration of AURK inhibitors, discussing their biological activities, structure-activity relationships, selectivity profiles, and mechanisms of action. Notably, compounds 6, 27, and 16 exhibit potent AURK-A inhibition with IC values of 1.7 nM, 11.83 nM, and 15 nM, respectively. Similarly, compounds 28, 16, and 7 demonstrate strong AURK-B inhibitory activity, with IC values of 10.5 nM, 12 nM, and 14.09 nM, respectively. This comprehensive overview aims to support medicinal chemists in developing more potent, selective, and safe AURK inhibitors as potential anticancer therapeutics.