Aurora kinase A
Aurora kinase A
Overview
Aurora kinase A (AURKA) is a serine/threonine kinase encoded by the AURKA gene and is a critical regulator of mitotic progression in mammalian cells. It localizes to the centrosome and mitotic spindle, where it orchestrates centrosome maturation, bipolar spindle assembly, and accurate chromosomal segregation during cell division. Beyond its canonical mitotic functions, AURKA participates in a range of non-mitotic processes including DNA damage response, regulation of transcription factor activity, and cellular stress adaptation. Dysregulation of AURKA — most commonly through gene amplification or protein overexpression — is observed across a broad spectrum of human malignancies, including breast, colorectal, head/neck, melanoma, ovarian, liver, and prostate tumors, establishing it as both an oncogenic driver and a high-priority therapeutic target.
Structurally, AURKA contains an N-terminal regulatory domain and a C-terminal catalytic kinase domain. Its activity is tightly controlled through phosphorylation at Thr288 and interaction with co-activators such as TPX2. In oncological contexts, AURKA overexpression promotes tumor progression through multiple mechanisms: driving genomic instability, sustaining proliferative signaling via pathways including PI3K/AKT/mTOR, suppressing tumor suppressors such as PTEN, and interacting with oncoproteins such as MYCN. This multifaceted oncogenic role, combined with its well-defined ATP-binding pocket, has made AURKA an attractive focus for small-molecule inhibitors and, more recently, targeted protein degradation strategies.
Focus of Latest Publications
Recent publications have expanded interest in Aurora kinase A beyond its canonical role in mitotic progression, highlighting both catalytic and non-catalytic functions. Several studies used Aurora kinase A as a therapeutic target in cancer drug discovery, including PROTAC-based degradation, hydrophobic tag degraders, and selective small-molecule inhibition. In parallel, bioinformatic and molecular docking analyses identified Aurora kinase A among hub targets in multi-omics cancer signatures, supporting its continued relevance in multi-target anticancer strategies.
A notable theme is the emerging importance of Aurora kinase A degradation rather than inhibition alone. One study showed that PROTAC-mediated depletion of Aurora kinase A caused profound S-phase defects and revealed a scaffolding function in the S phase, with interactome profiling identifying RNA-binding proteins, including DICER, as well as altered chromatin association of SETD2. The authors proposed a dual-output model in which Aurora kinase A helps recruit RNA-binding proteins to R-loops and simultaneously recruits SETD2 to support resolution of replicative stress. Another study reported the discovery of M9101, a potent, selective, and in vivo active Aurora kinase A PROTAC degrader derived from a promiscuous kinase inhibitor, with strong degradation potency in MD-MBA-231 cells and exceptional selectivity in global proteomic analysis. In a related degradation-focused effort, norbornene-based hydrophobic tag degraders were developed against Aurora kinase A, and the broader HyT strategy was used to map degradable kinases across the human kinome.
Other recent work examined Aurora kinase A inhibition in specific cancer contexts. VIC-1911, a next-generation ATP-competitive Aurora kinase A inhibitor, was shown to suppress growth of prostate cancer cells, induce mitotic failure, DNA double-strand breaks, and p53 pathway activation, and to sensitize tumors to PARP inhibition by inducing a functional BRCAness phenotype. In pancreatic ductal adenocarcinoma, Aurora kinase A overexpression was linked to radioresistance through interaction with GSK3β and inhibitory phosphorylation of PTEN at T366, leading to activation of the PI3K/AKT/mTOR pathway; this phenotype was reversed by GSK3β knockdown or a PTEN-T366A mutant. In lung cancer, Aurora kinase A overexpression was associated with reduced response to immune checkpoint blockade, and mechanistic studies showed that Aurora kinase A promoted T-lymphocyte apoptosis through the NOXA/p4E-BP1/MCL-1 axis, compromising PD-1/PD-L1-mediated immune responses.
Aurora kinase A also appeared in broader computational and translational studies of cancer therapeutics. Multi-representation machine learning and structural-alert analyses were used to screen Aurora kinase A and Aurora kinase B inhibitors, with the goal of improving selectivity. In hepatocellular carcinoma, Aurora kinase A was identified as one of five major hub genes, and quercetin was reported to downregulate its expression in HepG2 cells while inhibiting cell viability. Across these studies, Aurora kinase A remains a prominent target in cancer biology, with recent publications emphasizing its roles in cell-cycle control, replication stress, DNA repair, radioresistance, and immune evasion, as well as its tractability for both inhibition and targeted degradation.