Aurora Kinase Inhibitors Research Articles

Discovery of the first-in-class Aurora B kinase selective degrader.

Reversine is a small-molecule Aurora kinase inhibitor known for its pro-apoptotic effects and potential to remodel chromatin architecture. Although its impact on mitotic regulation is established, its effects on telomere dynamics and nuclear organization in chronic myeloid leukemia (CML) remain unclear. This study aimed to investigate the effects of reversine on telomere architecture, genomic instability, and apoptosis in CML cell lines (K-562 and MEG-01). Reversine was applied at increasing concentrations, and cytotoxicity was assessed using caspase-3/7 activation assays. Quantitative PCR was used to measure AURKA and AURKB mRNA expressions. Three-dimensional telomere architecture was analyzed with TeloView® v1.03 software after Q-FISH labeling to quantify telomere number, signal intensity, aggregation, nuclear volume, and a/c ratio. Reversine induced a dose- and time-dependent apoptotic response in both cell lines and significantly downregulated AURKA and AURKB expressions. Three-dimensional telomere analysis revealed a marked reduction in telomere number and aggregates, signal intensity, and nuclear volume. While reduced signal intensity may indicate telomere shortening, the concurrent decrease in aggregation and altered spatial parameters suggests telomeric reorganization rather than progressive instability. These features reflect structural nuclear remodeling and early apoptotic commitment. Differences between K-562 and MEG-01 responses underscore potential heterogeneity in telomere maintenance mechanisms. Reversine modulates genomic stability in CML cells through dual mechanisms involving Aurora kinase inhibition and telomere architecture remodeling. The integration of 3D telomere profiling highlights reversine’s potential as a therapeutic agent targeting nuclear disorganization and mitotic dysregulation in leukemia.

Design and synthesis of pyrazolopyrimidinone derivatives as dual VEGFR/Aurora kinase inhibitors against hepatocellular and breast carcinomas.

Kinases play critical roles in the development and adaptation of Plasmodium falciparum and present novel opportunities for chemotherapeutic intervention. Mitotic kinases that regulate the proliferation of the parasites by controlling nuclear division, segregation, and cytokinesis. We evaluated the potential of human Aurora kinase (Aur) inhibitors to prevent P. falciparum development by targeting members of the Aurora-related kinase (Ark) family in this parasite. Several human AurB inhibitors exhibited multistage potency (< 250nM) against all proliferative stages of parasite development, including asexual blood stages, liver schizonts, and male gametes. The most potent compounds, hesperadin, TAE684, and AT83, exhibited>1000x selectivity towards the parasite. Importantly, we identified PfArk1 as the principal vulnerable Ark family member, with specific inhibition of PfArk1 as the primary target for hesperadin. Hesperadin's whole-cell and protein activity validates it as a unique PfArk1 tool compound. Inhibition of PfArk1 results in the parasite's inability to complete mitotic processes, presenting with unsegregated, multi-lobed nuclei caused by aberrant microtubule organization. This suggests PfArk1 is the main Aur mitotic kinase in proliferative stages of Plasmodium, characterized by bifunctional AurA and B activity. This paves the way for drug-discovery campaigns based on hesperadin targeting PfArk1.

Chromosome congression is crucial for accurate cell division, with key roles played by kinetochore components, the molecular motor CENP-E/kinesin-7, and Aurora B kinase. However, Aurora B kinase can both inhibit and promote congression, suggesting the presence of a larger signaling network. Our study demonstrates that centrosomes inhibit congression initiation when CENP-E is inactive by regulating the activity of kinetochore components. Depletion of centrioles via Plk4 kinase inhibition allows chromosomes near acentriolar poles to initiate congression independently of CENP-E. At centriolar poles, high Aurora A kinase enhances Aurora B activity, increasing phosphorylation of microtubule-binding proteins at kinetochores and preventing stable microtubule attachments in the absence of CENP-E. Conversely, inhibition of Aurora A or expression of a dephosphorylatable mutant of the kinetochore microtubule-binding protein Hec1 enables congression initiation without CENP-E. We propose a negative feedback mechanism involving Aurora kinases and CENP-E that regulates the timing of chromosome movement by modulating kinetochore–microtubule attachments and fibrous corona expansion, with the Aurora A activity gradient providing critical spatial cues for the network’s function.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with a poor prognosis, necessitating the discovery of novel and reliable molecular biomarkers for improved clinical management. Traditional bulk transcriptomic analyses often mask the cellular heterogeneity and spatial complexity of the tumor microenvironment, limiting the identification of robust biomarkers. This study aimed to identify and validate key driver genes in HNSCC through a comprehensive multi-omics and machine learning-based approach. Transcriptomic data from multiple GEO datasets (GSE29330, GSE6631, GSE138206) and the TCGA-HNSC cohort were integrated and analyzed to identify consensus differentially expressed genes (DEGs). A suite of four machine learning algorithms (LASSO, SVM-RFE, XGBoost, Boruta) was employed to screen for core candidate genes. The cellular origins and spatial distribution of these core genes were subsequently dissected using public single-cell (GSE215403) and spatial transcriptomics (GSE252265) data. Finally, the expression of the key gene, SASH1, was validated at the protein level via Western blot in HNSCC cell lines, and its clinical and therapeutic value was assessed through survival, clinical correlation, and drug sensitivity analyses. An integrated analysis of bulk transcriptomic data identified 159 consensus DEGs, from which four core genes (COL1A1, EMP1, MYH11, SASH1) were robustly selected by all four machine learning algorithms. Multi-omics validation revealed that SASH1 was specifically downregulated within the malignant cell population and its expression was spatially exclusive from the COL1A1-high fibrotic stromal regions. Western blot confirmed the significant downregulation of SASH1 protein in HNSCC cells compared to controls. Importantly, low SASH1 expression was significantly associated with poorer overall survival in the TCGA cohort (p<0.05), a prognostic value not observed for the other core genes. Functional analyses linked SASH1 to critical pathways including cell cycle and adhesion. Furthermore, SASH1 expression levels correlated with sensitivity to multiple targeted drugs, including ATR and Aurora kinase inhibitors. By systematically integrating multi-platform transcriptomics, machine learning, and multi-dimensional validation, this study identifies SASH1 as a robust prognostic biomarker and a potential predictor of therapeutic response in HNSCC. The established multi-omics pipeline provides a meaningful framework for biomarker discovery and highlights SASH1 as a promising target for advancing precision medicine in HNSCC.

The spindle assembly checkpoint (SAC) delays the metaphase-to-anaphase transition. Aurora kinase A (AURKA) inactivation has been shown to cause premature exit from mitosis in the presence of an unsatisfied SAC. We report for the first time that centromeric AURKA interacts with survivin during prometaphase. Notably, depleting or inhibiting AURKA activity at this stage causes mislocalisation of the CPC and BubR1, which compromises the SAC and can lead to mitotic slippage. Furthermore, we show that AURKA binds directly to the BIR domain of survivin at a position distinct from AURKB and indirectly to it via its C terminus. We find the interaction peaks during prometaphase but persists into late mitosis. Importantly, we demonstrate that cells with high levels of survivin are particularly vulnerable to mitotic slippage induced by the AURKA inhibitor, MLN8237/ Alisertib. Alisertib enables both normal and transformed cells with high levels of survivin to activate the APC/C prematurely, as observed by the destruction of cyclin B and securin. Thus, a high expression of survivin can alter cell fate decisions at mitosis and lead to genetic instability, a key hallmark in cancer.

Aurora kinase A, a serine-threonine kinase frequently overexpressed in cancers, remains unaddressed by clinically approved inhibitors. Our previously endeavors unveiled a unique class of quinazolin-4-amine derivatives as potent, selective Aurora A kinase inhibitors. To further enhance therapeutic potential and Aurora A selectivity, we conducted systematic structural optimization and developed compound 5h, which exhibits potent antiproliferative activity across human cancer cell linesparticularly in triple-negative breast cancer MDA-MB-231 cells. Crucially, 5h exhibits 362-fold selectivity for Aurora A over Aurora B, a critical feature for therapeutic efficacy and safety. Molecular dynamics simulations reveal its selectivity arises from unique C-H/π interactions, enhanced hydrophobic contacts, an open Aurora A binding pocket, and tighter protein packing. At submicromolar concentrations, 5h effectively suppresses Aurora A autophosphorylation. Furthermore, it significantly inhibits tumor growth in MDA-MB-231 xenograft models, supporting its development as a promising anticancer candidate.

[This retracts the article DOI: 10.2147/DDDT.S74127.].

BackgroundLung adenocarcinoma shows distinct differences between males and females in incidence, prognosis, and treatment response, suggesting unique molecular mechanisms that remain underexplored. This study aims to identify sex-specific molecular signatures and therapeutic targets in lung adenocarcinoma using multi-omics approaches to inform personalized treatment strategies.MethodsWe conducted an integrative analysis of transcriptomic and proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) datasets, comparing male and female lung adenocarcinoma profiles. Transcription factor activity was assessed using TIGER on gene expression data, while kinase activity was evaluated with PTM-SEA on proteomic data. These results were combined to build a kinase-transcription factor signaling network. Potential sex-specific drugs were identified using the PRISM drug screening database.ResultsThe analysis revealed significant sex-based differences in transcription factor and kinase activity. Notably, NR3C1, AR, and AURKA exhibited sex-biased expression and activity. The constructed signaling network highlighted druggable pathways linked to cancer-related processes, with distinct profiles in males and females. PRISM screening identified glucocorticoid receptor agonists and aurora kinase inhibitors as promising sex-specific therapeutic candidates.ConclusionsOur findings underscore the importance of considering sex differences in lung adenocarcinoma molecular profiles. The integration of transcriptomic and proteomic data reveals sex-specific pathways and potential therapies, paving the way for personalized treatment approaches tailored to male and female patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13293-025-00752-1.

Aurora kinase A inhibition as a synthetic lethality strategy in ARID1A-mutated gastroenteropancreatic neuroendocrine carcinoma.

This work describes the discovery of a new series of Aurora kinase inhibitors based on quinazoline skeleton derived from ENMD-2076, as well as the first X-ray cocrystal structure complexes of vinyl-quinazoline 9h with Aurora A. Replacing pyrimidine with quinazoline improved anticancer activity and facilitated cocrystal formation. Compounds 9a and 9h showed excellent Aurora A kinase inhibition, with IC50 values of 6.0 and 2.8 nM, respectively. 9h demonstrated superior activity against TNBC MDA-MB-231 cells with an IC50 value of 48 nM and achieved 59% tumor growth inhibition in xenograft models, vs ENMD-2076's 33% with no observable toxicity. Mechanistic studies using immunoblotting, immunofluorescence staining, and flow cytometry showed that 9h outperforms ENMD-2076 in inhibiting Aurora A kinase activation, preventing spindle formation, arresting the cell cycle, and inducing cell apoptosis. Thus, 9h has the potential for further optimization and is a promising anticancer drug candidate.

Aurora kinases are a group of serine/threonine kinases essential for cell mitosis, comprising Aurora A, B, and C.However, the Aurora B is overexpressed in multiple tumors and the aurone has been proved to exhibit potent inhibitory activity against Aurora B kinase by our group. The indolinone was considered as an aurone scaffold hopping analog, and the indolinone-based Aurora B inhibitor library (3577 molecules) was constructed by FBDD strategy. After pharmacophore model and molecular docking, the candidate molecules were identified, then synthesized via Suzuki-Miyaura and Knoevenagel reactions. The compounds 3-17a, 3-17d and 3-17k especially inhibited Aurora B in the nanomolar range (IC50 = 1.100, 1.518 and 0.8911nM, respectively), showing no significant inhibition of Aurora A. Notably, the most potent 3-17k demonstrated the strongest antiproliferative activity against HGC27 (IC50 = 2.05μM) and HT-29 (IC50 = 2.07μM) cell lines, as well as Aurora B over-expression cells, including OVCAR8 (IC50 = 3.02μM), T24 (IC50 = 10.21μM), NCIH1299 (IC50 = 7.32μM) and SW480 (IC50 = 4.45μM), while maintaining a lower cytotoxicity in normal human cells (GES-1 and NCM460). Additionally, molecular dynamics simulation were conducted to explore the binding interactions between 3-17k and Aurora B (PDB: 5EYK), revealing favorable binding free energy (-33.34kcal·mol-1). Based on available data, compound 3-17k warrants comprehensive investigation to evaluate its potential as an anticancer drug candidate.

Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in cell cycle regulation, particularly during mitosis. Recent studies have identified AURKA as an oncogene overexpressed in various cancers, including gastric cancer (GC). This review summarizes the molecular mechanisms by which AURKA contributes to GC pathogenesis, including its roles in cell proliferation, apoptosis inhibition, epithelial-mesenchymal transition (EMT), and cancer stemness. AURKA regulates key signaling pathways such as PI3K/Akt, Wnt/β-catenin, NF-κB, and JAK2/STAT3, promoting tumor growth, metastasis, and therapy resistance. Additionally, AURKA interacts with critical tumor suppressors like p53 and PTEN, further enhancing its oncogenic potential. Clinical studies have demonstrated that AURKA overexpression correlates with poor prognosis in GC patients, highlighting its potential as a diagnostic and therapeutic target. This review also discusses the efficacy of AURKA inhibitors in preclinical settings, offering insights into their therapeutic potential. By elucidating the multifaceted roles of AURKA in GC, this review aims to provide a comprehensive understanding of its mechanisms and implications for future research and treatment strategies.

Targeting Aurora A kinase: Computational discovery of potent inhibitors through integrated pharmacophore and simulation approaches.

First-in-class dual inhibitors of MASTL and Aurora A kinase: Discovery of selective cyclohexa[b]thiophenes with potent anticancer activity.

Gastric cancer was the fifth most common cancer, and its drug treatment mainly included chemotherapy, targeted therapy, and immunotherapy. With the rise of immunotherapy in gastric cancer, small-molecule anti-gastric cancer drugs still have irreplaceable places because of many advantages, such as high stability and mass-productivity, high efficiency, and low cost. At present, the small-molecule anti-gastric cancer drugs in the clinic are constrained by their side effects. So, developing more novel anti-gastric cancer drugs with better efficacy and fewer side effects is urgently needed. Nitrogen-containing heterocycle molecules have attracted much attention from researchers due to their high biocompatibility, activity, and bioavailability, and they even could act with a unique mechanism. This review summarized various types of nitrogen-containing heterocycle antigastric cancer lead compounds from 2017 to 2022 in the last five years. Compared with monocyclic nitrogen-containing heterocycle and bicyclic nitrogen-containing heterocycle, the thick nitrogen-containing heterocycle applied as the skeleton not only showed high efficiency and low toxicity but also, interestingly, may have had some unique mechanism such as inhibition of aurora A and B kinases, etc. We propose two prospective and valuable strategies to develop more efficient candidates for anti-gastric cancer. One strategy was further optimized for some lead compounds mentioned in this review. The other strategy involved utilizing the "pseudo-natural products" concept proposed by Professor Herbert Waldmann, combining different nitrogen-containing heterocycle fragments in two and three-dimensional spaces to obtain new thick nitrogen-containing heterocycle skeletons. The strategy will contribute to the expansion of the thick nitrogenous heterocycle's framework, and it was expected that more novel mechanisms and more effective antigastric drugs could be found. These two strategies are expected to help researchers develop more anti-gastric cancer drugs with better potency and lower side effects.

Alisertib inhibits acute myeloid leukemia cell growth by inhibiting STAT3 activation.

Osteoarthritis (OA) is a common joint disease, and chondrocyte extracellular matrix (ECM) degradation was closely associated with its progression. This study investigated the regulatory mechanisms of ECM degradation during OA development. A rat model of OA was established by anterior cruciate ligament transection (ACL-T) and interleukin-1 beta (IL-1β)-stimulated rat chondrocytes were used to simulate OA invitro. Cartilage damage was evaluated by hematoxylin-eosin (HE) and safranin O-fast green staining. The ECM content in chondrocytes was assessed by alcian blue staining. Real-time quantitative PCR (RT-qPCR), Western Blotting, immunohistochemical staining, and immunofluorescent staining were adopted to analyze associated molecule expression. Molecular mechanisms were elucidated by Co-immunoprecipitation (Co-IP) and GST pull-down assay. We found that Aurora kinase A (AURKA), p-eukaryotic translation initiation factor 4E (eIF4E), and ADAM metallopeptidase with thrombospondin type 1 motif 12 (ADAMTS12) levels were elevated in the human and rat cartilage tissues of OA, as well as IL-1β-exposed chondrocytes. AURKA inhibition restrained ECM degradation to relieve OA via down-regulation of ADAMTS12. AURKA overexpression phosphorylated eIF4E, which promoted cap-dependent translation of ADAMTS12. Moreover, DNA methyltransferase 1 (DNMT1)-mediated methylation down-regulated HECT domain E3 ubiquitin protein ligase 1 (HECTD1) in the OA model and consequently enhanced AURKA expression via inhibiting its ubiquitination. HECTD1 knockdown or ubiquitination repression intensified ECM degradation in IL-1β-stimulated chondrocytes. Taken together, low expression of HECTD1 repressed AURKA ubiquitination to elevate AURKA protein level and subsequently facilitated eIF4E-mediated cap-dependent translation of ADAMTS12, thus resulting in ECM degradation during OA progression.

BackgroundHepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. It is often diagnosed at advanced stages, which limits treatment options. Although Donafenib is a standard therapy for advanced HCC, its effectiveness is often reduced by treatment failures. Alisertib, an Aurora-A kinase inhibitor, shows promise in enhancing the cytotoxic effects of Donafenib. This study investigates the combined therapeutic effects of these two agents.MethodsSynergistic cytotoxicity was assessed via CCK-8 and colony formation assays. Ferroptosis activation was quantified through flow cytometry, lipid peroxidation, and measurements of reactive oxygen species (ROS), intracellular Fe2+, and GSH/GSSG. Mechanistic studies involved immunofluorescence for NF-κB/p65 localization, along with Western blotting, qPCR, and dual-luciferase reporter assays to evaluate protein and gene expression. Chromatin immunoprecipitation (ChIP) experiments were performed to analyze the binding of NF-κB/p65 to its endogenous promoters. In vivo xenografts were established to evaluate the antitumor efficacy and potential side effects of the combination treatment, supported by histological and immunohistochemical analyses.ResultsOptimal synergistic concentrations (Alisertib 2.5 µM + Donafenib 10 µM for HCCLM3; 5 µM for Huh7) induced profound ferroptotic cascades, evidenced by elevated ROS, lipid peroxides, and Fe2+ accumulation concurrent with GSH depletion. The co-treatment potently inhibited p65 nuclear translocation while stabilizing IκBα, thereby suppressing NRF2-mediated antioxidant transcription. Xenograft models demonstrated marked tumor volume reduction with preserved organ architecture and hematological parameters, confirming clinical translatability.ConclusionAlisertib is identified as a potent enhancer of Donafenib-induced ferroptosis through inhibition of the NF-κB/NRF2 pathway. This suggests a novel combinatorial strategy that targets ferroptosis through NF-κB inhibition. Further research is needed to translate these promising results into clinical practice.