Aurora Kinase Research Articles

AI-Assisted Generation and In-depth In-silico Evaluation of Potential Inhibitor Targeting Aurora Kinase A (AURKA): An Anticancer Discovery Exploiting Synthetic Lethality Approach

Genetic alterations are lead causative agents behind the complex pathologies of cancers which render all treatments unarmed. Such alterations in oncogenes can be treated by direct inhibition by specific drugs while alteration in tumor suppressor genes mediating loss of function is challenging to treat. Identification of synthetic lethal partners to specific tumor suppressor genes and mediating their inhibition can be a potential approach to deal with loss of function mutations. Aurora kinase A (AURKA) has been established as an effective synthetic lethal partner of several tumor suppressor genes and is overexpressed in cancerous conditions, mediating adverse pathologies. The present AI-assisted study deals with the generation of novel inhibitor compounds against AURKA and the exhaustive evaluation of the best compound using molecular docking, molecular dynamic simulation, MM/PBSA, and QM/MMGBSA-based analysis. Out of the 200 novel compounds generated using features of ATP binding pocket of AURKA and previously reported inhibitor, compound 1 (4-{5-fluoro-6-[(1Z)-3-hydrazinyl-3-oxo-2-phenylprop-1-en-1-yl]pyridin-2-yl}benzoic acid) was identified as the most potent candidate with high negative binding energy of -10.4 kcal/mol in molecular docking analysis. The molecular dynamic simulation analysis of the AURKA-compound 1 complex and the apo-AURKA protein resulted in major conformational changes in the conserved DFG motif and loop 277-291 of AURKA in the AURKA-compound 1 complex thus inhibiting the entry of ATP to its binding site. The free energy landscape displayed a persistence of folded states of the enzyme in complex form. The MM/PBSA revealed effective Gibb’s free energy of binding of -11 kcal/mol for compound 1 inhibiting AURKA. The QM/MMGBSA analysis resulted in a significantly high negative binding energy of -13.98 kcal/mol proving significant inhibition potential of compound 1 against AURKA. Therefore, further in-vitro investigation can provide a novel effective, and safe treatment against a wide range of cancers by targeting a well-established cancer target AURKA.

Aurora kinase as a putative target to tick control.

Aurora kinases (AURK) play a central role in controlling cell cycle in a wide range of organisms. They belong to the family of serine-threonine kinase proteins. Their role in the cell cycle includes, among others, the entry into mitosis, maturation of the centrosome and formation of the mitotic spindle. In mammals, 3 isoforms have been described: A, B and C, which are distinguished mainly by their function throughout the cell cycle. Two aurora kinase coding sequences have been identified in the transcriptome of the cattle tick Rhipicephalus microplus (Rm-AURKA and Rm-AURKB) containing the aurora kinase-specific domain. For both isoforms, the highest number of AURK coding transcripts is found in ovaries. Based on deduced amino acid sequences, it was possible to identify non-conserved threonine residues which are essential to AURK functions in vertebrates and which are not present in R. microplus sequences. A pan AURK inhibitor (CCT137690) caused cell viability decline in the BME26 tick embryonic cell line. In silico docking assay showed an interaction between Aurora kinase and CCT137690 with exclusive interaction sites in Rm-AURKA. The characterization of exclusive regions of the enzyme will enable new studies aimed at promoting species-specific enzymatic inhibition in ectoparasites.

Post-transcriptional control drives Aurora kinase A expression in human cancers.

Aurora kinase A (AURKA) is a major regulator of the cell cycle. A prominent association exists between high expression of AURKA and cancer, and impairment of AURKA levels can trigger its oncogenic activity. In order to explore the contribution of post-transcriptional regulation to AURKA expression in different cancers, we carried out a meta-analysis of -omics data of 18 cancer types from The Cancer Genome Atlas (TCGA). Our study confirmed a general trend for increased AURKA mRNA in cancer compared to normal tissues and revealed that AURKA expression is highly dependent on post-transcriptional control in several cancers. Correlation and clustering analyses of AURKA mRNA and protein expression, and expression of AURKA-targeting hsa-let-7a miRNA, unveiled that hsa-let-7a is likely involved to varying extents in controlling AURKA expression in cancers. We then measured differences in the short/long ratio (SLR) of the two alternative cleavage and polyadenylation (APA) isoforms of AURKA mRNA across cancers compared to the respective healthy counterparts. We suggest that the interplay between APA and hsa-let-7a targeting of AURKA mRNA may influence AURKA expression in some cancers. hsa-let-7a and APA may also independently contribute to altered AURKA levels. Therefore, we argue that AURKA mRNA and protein expression are often discordant in cancer as a result of dynamic post-transcriptional regulation.

ANGI-14. DRUGGABLE GENOME CRISPR SCREEN IN 3D HYDROGEL DEVICES REVEALS TARGETABLE KINASES AND PHOSPHATASES IMPLICATED IN CYTOSKELETAL REORGANIZATION IN INVADING GBM CELLS

Abstract The invasive nature of glioblastoma cells into adjacent brain tissues is a key factor in its unfavorable prognosis. To decipher the mechanisms driving glioblastoma invasion, we developed microdissectable biomimetic 3D hydrogel invasion devices containing hyaluronic acid hydrogels decorated with integrin-binding peptides (RGD) and crosslinked with protease-cleavable crosslinkers. The ability to disassemble these devices and interrogate cells in the core vs. invasive fraction allows for high throughput screens. We thus performed a screen in GBM43 cells expressing CRISPR/Cas9 and a 13,250 gRNA library targeting the 2550 genes in the druggable human genome. Of seven initial hits from this screen, only two could be validated by single gene CRISPR and use of a drug to target the hit - ACP1 (also known as LMW-PTP) and Aurora Kinase B (AURKB). Integration of ChIP-seq and RNA-seq revealed no plausible transcriptional targets of ACP1 and AURKB that could drive invasion. Proximity labeling with the TurboID system identified CTTN (cortactin), an actin binding protein whose phosphorylation is integral to the formation of lamellipodia and invadopodia, as phosphorylated by AURKB and Ephrin A2 (EPHA2), whose dephosphorylation controls cell morphology, adhesion, migration and invasion by modifying the organization of the actin cytoskeleton and influencing the activities of integrins and intercellular adhesion molecules, as dephosphorylated by ACP1. These findings underscore the delicate balance between kinase and phosphatase activities in regulating the actin cytoskeleton broadly and at the cell’s front or “leading edge,” offering new therapeutic targets to disrupt the invasion that is a hallmark of glioblastoma.

The ncRNA-AURKA Interaction in Hepatocellular Carcinoma: Insights into Oncogenic Pathways, Therapeutic Opportunities, and Future Challenges

Hepatocellular carcinoma (HCC) represents a major public health concern and ranks among the leading cancer-related mortalities globally. Due to the frequent late-stage diagnosis of HCC, therapeutic options remain limited. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) in the regulation of Aurora kinase A (AURKA), one of the key hub genes involved in several key cancer pathways. Indeed, the dysregulated interaction between ncRNAs and AURKA contributes to tumor development, progression, and therapeutic resistance. This review delves into the interplay between ncRNAs and AURKA and their role in hepatocarcinogenesis. Recent findings underscore the involvement of the ncRNAs and AURKA axis in tumor development and progression. Furthermore, this review also discusses the clinical significance of targeting ncRNA-AURKA axes, offering new perspectives that could lead to innovative therapeutic strategies aimed at improving outcomes for HCC patients.

Chemical genetics analysis suggests the involvement of Aurora kinase and MAPKs in aluminum-induced malate secretion in Arabidopsis.

Chemical genetics is a multidisciplinary research method. In this study, it is used to screen compounds that promote aluminum-induced malate secretion in Arabidopsis thaliana. Inhibition of p38 mitogen-activated protein kinase (p38 MAPK; LY2228820) significantly increased the transcription of Arabidopsis thaliana aluminum-activated malate transporter 1 (AtALMT1) and sensitive to proton rhizotoxicity 1 (STOP1)-regulated genes, multidrug and toxic compound extrusion and aluminum sensitive 3, but not AtSTOP1 and the Al-biomarker genes At3g28510, At5g13320, suggesting that LY2228820 increased the early expression of STOP1-regulated genes without affecting AtSTOP1 expression. Inhibition of p38 MAPK (LY2228820) and Aurora A (MLN8237) increased aluminum-activated malate transport via AtALMT1, suggesting that both MLN8237 and LY2228820 interfere with AtALMT1 activity. An increase in root elongation was also observed in Arabidopsis after applying compounds LY2228820 and MLN8237. Thus, both LY2228820 and MLN8237 may play important roles in alleviating the inhibitory effects of aluminum on roots.

Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals.

Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)-induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux-orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8+ T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy.

Recent advancements in mechanistic Research, therapeutic Potential, and Structure-Activity relationships of Aurora kinase inhibitors in cancer therapies

Recent advancements in mechanistic Research, therapeutic Potential, and Structure-Activity relationships of Aurora kinase inhibitors in cancer therapies

Development of 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases.

Monopolar spindle 1 (Mps1, also known as TTK) and Aurora kinase (AURK) A and B are critical regulators of mitosis and have been linked to the progression of various cancers. Here, we report the design, synthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting chimeras) targeting TTK and AURKs. We synthesized various degrader molecules based on four different 2-aminoadenine-based ligands, recruiting either cereblon or VHL as the E3-ligase. Our research showed that the nature of the linker and modification of the ligand significantly influence the target specificity and degradation efficacy. Notably, compound 19, among the most potent degraders, demonstrated robust proteasome-mediated degradation of TTK with D max of 66.5% and DC50 value (6 h) of 17.7 nM as compared to its structurally akin inhibitor control, 23. The cytotoxicity of most of the synthesized chimeras against acute myeloid leukemia cell line MV4-11 was lower than that of the corresponding parent inhibitors. However, we could also identify degraders such as 15 and 26 that induce potent AURKA degradation and display comparable antiproliferative activities to their parent compound SF1. Compound 15 degrades AURKA with low DC50 value of 2.05 nM, which is 77-fold and 21-fold more selective toward AURKB and TTK and has an EC50 value of 39 nM against cancer MV4-11 cells. Overall, the observations we made with the degrader molecules we developed can further aid in the design and development of optimized TTK or AURK degraders for cancer therapy.

Aurora B/AIR-2 regulates sister centromere resolution and CENP-A/HCP-3 organization to prevent merotelic attachments.

During cell division, the accurate capture of sister kinetochores that are built on the centromeres of chromosomes by microtubules emanating from opposite spindle poles governs faithful chromosome segregation. To ensure sister chromatids separate correctly, sister centromeres undergo resolution to achieve bi-polar orientation prior to microtubule attachments. Failure of centromere resolution increases the frequency of merotelic attachments, with microtubules from opposite poles attaching to the same sister kinetochore, causing lagging chromosome, aneuploidy, and even cancer progression. The Aurora B-mediated tension-sensing machinery to correct erroneous kinetochore-microtubule attachments has been well studied. However, preventative mechanisms to avoid merotelic attachments that occur in the earlier mitotic stage are poorly understood. In this study, we found that inactivation of mitotic kinase Aurora B/AIR-2 increases merotelic attachments in Caenorhabditis elegans. On one hand, Aurora B/AIR-2-deficient cells exhibited a delay in the occurrence of centromere resolution and a disruption in targeting condensin II components to chromatin. On the other hand, loss of Aurora B/AIR-2 results in an increased localization of centromeric proteins CENP-A/HCP-3 and M18BP1/KNL-2 as well as the kinetochore protein MIS-12 on chromatin, which may generate ectopic kinetochores causing erroneous attachments. To conclude, this study elucidated that Aurora B/AIR-2 regulates sister centromere resolution and CENP-A/HCP-3 deposition to actively prevent merotely and chromosome instability in cells.

AURKA inhibition shows promise as a therapeutic strategy for ARID1A-mutant colorectal cancer

PurposeMutations in ARID1A frequently occur in colorectal cancer (CRC) cells. However, there are currently no clinical treatment options specifically addressing this aberration. The preliminary in vitro experiments revealed a synthetic lethal interaction between ARID1A and Aurora kinase A (AURKA) in colorectal cancer (CRC) cells.MethodsWe collected samples from 80 CRC patients and evaluated the efficacy of AURKA inhibitor (AURKAi) using the ATP-tumor chemosensitivity assay (ATP-TCA) on untreated ARID1A-proficient (ARID1A +) and ARID1A-deficient (ARID1A-) CRC patient samples. In addition, we validated this result by a clonogenic assay. Additionally, we examined the effects of AURKA inhibitors on cell cycle progression and apoptosis in ARID1A + and ARID1A- CRC patient samples using flow cytometry.ResultsThe results showed that AURKAi selectively inhibited the growth of ARID1A- CRC cells. Furthermore, AURKA inhibitors significantly increased G2/M arrest and induced apoptosis in ARID1A- cells.ConclusionWe believe that AURKAi hold promise as potential therapeutics for ARID1A mutation colorectal cancer patients.

Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells

The protein kinases DYRK1A and DYRK1B are pivotal regulators of cell cycle progression by promoting cell cycle exit into quiescence. DYRK1B appears to play a more important role in cancer cell quiescence than DYRK1A, as evidenced by its overexpression or copy number variations in human tumour samples. Nonetheless, the stimuli driving DYRK1B upregulation and the potential divergence in expression patterns between DYRK1A and DYRK1B remain largely elusive. In the present study, we scrutinized the regulatory pathways modulating DYRK1B expression relative to DYRK1A in PANC-1 and A549 cancer cell lines across varying conditions. Serum deprivation, pharmacological mTOR inhibition and increased cell density resulted in the differential upregulation of DYRK1B compared to DYRK1A. We then aimed to assess the role of protein kinases MST1 and MST2, which are key transmitters of cell density dependent effects. Unexpectedly, exposure to the MST1/2 inhibitor XMU-MP-1 resulted in increased DYRK1B levels in A549 cells. Further investigation into the off-target effects of XMU-MP-1 unveiled the inhibition of Aurora kinases (AURKA and AURKB) as a potential causative factor. Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases.

Cell cycle inhibitors activate hypoxia-induced DDX41-STING pathway to mediate anti-tumor immune response in liver cancer.

Cell cycle inhibitors have a long history as cancer treatment. Here, we reported that these inhibitors combated cancer partially via Stimulator of IFN genes (STING) signaling pathway. We demonstrated that Paclitaxel (microtubule stabilizer), Palbociclib (cyclin dependent kinase 4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anti-cancer functions beyond arresting cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic HCC cells more sensitive to the anti-mitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment of cell cycle inhibitors, especially Paclitaxel, extends survival by perturbing mouse HCC growth when used in combination with anti-PD-1. We observed a trend that Paclitaxel suppressed STINGWT HCC more effectively than STINGKO HCC, suggesting that STING might contribute to the anti-tumor effects of Paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

8672 Disrupted Glucocorticoid Receptor Mediated Signalling Causes a Primary Cilia Defect in the Fetal Mouse Renal Tubule

Abstract Disclosure: J. Lao: None. K.L. Short: None. J. Ng: None. D.L. Cottle: None. T.J. Cole: None. Primary cilia are microtubule-based organelles that protrude from cell membranes to mediate diverse developmental signalling pathways and senses extracellular stimuli to maintain tissue homeostasis. We show that glucocorticoid (GC) signalling via the glucocorticoid receptor (GR) is a regulator of normal primary cilia formation in kidney renal tubules. RNA sequencing of whole E18.5 fetal kidney from mice with global deletion of the GR (GR-null) compared to littermate wild-type controls identified significantly reduced mRNA levels of key ciliogenesis-related genes. Further analysis of whole fetal kidney RNA by real-time-qPCR confirmed reduced mRNA levels for the cilia-associated proteins Ccp110 (fold -2.18), Cep97 (fold -1.78), Cep290 (fold -2.91), Kif3a (fold -1.82) and Rpgr (fold -1.90). Confocal microscopy revealed abnormal, stunted primary cilia in renal proximal tubules, collecting ducts and podocytes in GR-null or in renal tubule conditional GR-deleted mice, created using the HoxB7 Cre-driver allele. Primary cilia length was significantly decreased in kidney proximal tubule cells in GR-null mice (5.01 ± 0.11μm) compared with wildtype controls (6.20 ± 0.15μm). Furthermore, scanning electron microscopy of E18.5 GR-null kidney further confirmed aberrant primary cilia morphology in the proximal renal tubules and the absence of an apical brush border. Activation of GR signalling with the synthetic GC dexamethasone in cultured mouse IMCD3 kidney tubule cells significantly increased primary cilia length (2.89 ± 0.04μm) compared to vehicle controls (2.46 ± 0.28μm), an effect blocked by the GR antagonist RU486 (vehicle + RU486: 2.06 ± 0.02μm, dexamethasone + RU486: 2.00 ± 0.02μm). Aurora kinase A (AURKA) is a known regulator of primary cilia formation via the AKT cell signalling pathway and distinct proteins at different stages of the mitotic cell cycle. AURKA protein levels were downregulated in GR-null kidney and in IMCD3 cells which suggest GR regulates AURKA to control the assembly and disassembly of primary cilia. Together, these results demonstrate that GC signalling via the GR is required for normal primary ciliogenesis in the developing renal tubule and suggests that synthetic GR agonists may provide a novel therapeutic option for human ciliopathies such as those observed in forms of polycystic kidney disease. Presentation: 6/2/2024

Robust approach for production of the human oncology target Aurora kinase B in complex with its binding partner INCENP

Protein kinases are key players in many eukaryotic signal transduction cascades and are as a result often linked to human disease. In humans, the mitotic protein kinase family of Aurora kinases consist of three members: Aurora A, B and C. All three members are involved in cell division with proposed implications in various human cancers. The human Aurora kinase B has in particular proven challenging to study with structural biology approaches, and this is mainly due to difficulties in producing the large quantities of active enzyme required for such studies. Here, we present a novel and E. coli-based production system that allows for production of milligram quantities of well-folded and active human Aurora B in complex with its binding partner INCENP. The complex is produced as a continuous polypeptide chain and the resulting fusion protein is cleaved with TEV protease to generate a stable and native heterodimer of the Aurora B:INCENP complex. The activity, stability and degree of phosphorylation of the protein complex was quantified by using a coupled ATPase assay, 31P NMR spectroscopy and mass spectrometry. The developed production system enables isotope labeling and we here report the first 1H–15N-HSQC of the human Aurora B:INCENP complex. Our developed production strategy paves the way for future structural and functional studies of Aurora B and can as such assist the development of novel anticancer drugs targeting this important mitotic protein kinase.

Paeoniae radix overcomes resistance to EGFR-TKIs via aurora B pathway suppression in lung adenocarcinoma

Targeted therapies using epidermal growth factor receptor (EGFR) inhibitors have markedly improved survival rates and quality of life for patients with EGFR-mutant lung adenocarcinoma (LUAD). Despite these advancements, resistance to EGFR inhibitors remains a significant challenge, limiting the overall effectiveness of the treatment. This study explored the synergistic effects of combining Paeoniae Radix (PR) with first-generation EGFR-tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, to overcome this resistance. Transcriptomic analysis of EGFR-mutant LUAD cell lines revealed that PR treatment could potentially reverse the gene signatures associated with resistance to EGFR-TKIs, primarily through the suppression of the Aurora B pathway. Experimental validation demonstrated that combining PR with erlotinib and gefitinib enhanced drug responsiveness by inhibiting Aurora kinase activity and inducing apoptosis in LUAD cells. Additionally, gene expression changes confirmed these combined effects, with the suppression of the Aurora B pathway and upregulation of the apoptotic pathway, which was accompanied by increased expression of multiple pro-apoptotic genes. Our findings contribute to the development of natural product-based therapeutic strategies to mitigate drug resistance in LUAD.

Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis.

This study investigated the effect of forkhead box M1 (FOXM1) and Aurora kinase B (AURKB) on the epidermal function of keratinocytes. Bioinformatics analysis was used to analyze the co-expression network of FOXM1 and its correlation with AURKB. The expression of FOXM1 and AURKB in tissues and cells was detected by immunofluorescence and real-time quantitative polymerase chain reaction, respectively. HaCaT cells were transfected with si-FOXM1 to knock down FOXM1. Cell proliferation was detected by cell counting kit-8 assay. Cell migration was detected by scratch assay. Cell invasion was detected by the Transwell invasion assay. Cell apoptosis and cell cycle were detected by flow cytometry. FOXM1 and AURKB were positively correlated and highly expressed in psoriatic lesions. After transfection of si-FOXM1, the expression levels of FOXM1 and AURKB genes significantly decreased. The proliferation of HaCaT cells decreased, the apoptosis rate increased significantly, and the proportion of cells in the G1 phase increased significantly, while the proportion of cells in the S phase decreased significantly. The scratch closure of HaCaT cells was reduced, and the number of cell invasions decreased significantly. FOXM1 and AURKB may affect the progression of psoriasis by regulating the proliferation, cell cycle, migration, and invasion of keratinocytes.

Helicobacter pylori VacA-induced mitochondrial damage in the gastric pit cells of the antrum and therapeutic rescue

Exploring host cell specificity, pathogenicity, and molecular mechanisms of the vacuolating cytotoxin A (VacA), secreted by Helicobacter pylori (Hp) is crucial for developing novel treatment strategies. VacA affects subcellular events, particularly mitochondria, at a cell-type-specific level. However, the lack of reliable models that mimic VacA-induced subcellular damages and enable novel drug screening linked to the human stomach clinically limits our understanding of the mitochondrial networks in vivo. Here, human antrum gastric organoids (hAGOs) and tissue samples from Hp-infected patients were used to show the toxic effects of VacA-induced mitochondrial damage mainly in mucus-producing gastric pit cells by employing transcriptional, translational, and functional analyses. In VacA-intoxicated or Hp-infected hAGOs, robust mitochondrial fragmentation in gastric pit cells reduced ATP production during respiration, and loss of mucosal barrier integrity was first demonstrated experimentally. Using hAGOs, clinically relevant small molecules were screened for efficacy, and MLN8054, an Aurora kinase A inhibitor, reversed VacA-induced mitochondrial damage and loss of gastric epithelium integrity. MLN8054 was effective in VacA-treated and Hp-infected hAGOs and mice, highlighting hAGOs as a promising drug-screening model. These findings suggest that mitochondrial quality control may serve as a promising therapeutic target for Hp VacA-mediated toxicity and disease progression.

Genetic interaction mapping of Aurora protein kinases in mouse oocytes.

The Aurora Kinases (AURKs) are a family of serine-threonine protein kinases critical for cell division. Somatic cells express only AURKA and AURKB. However, mammalian germ cells and some cancer cells express all three isoforms. A major question in the field has been determining the molecular and cellular changes when cells express three instead of two aurora kinases. Using a systematic genetic approach involving different Aurora kinase oocyte-specific knockout combinations, we completed an oocyte-AURK genetic interaction map and show that one genomic copy of Aurka is necessary and sufficient to support female fertility and oocyte meiosis. We further confirm that AURKB and AURKC alone cannot compensate for AURKA. These results highlight the importance of AURKA in mouse oocytes, demonstrating that it is required for spindle formation and proper chromosome segregation. Surprisingly, a percentage of oocytes that lack AURKB can complete meiosis I, but the quality of those eggs is compromised, suggesting a role in AURKB to regulate spindle assembly checkpoint or control the cell cycle. Together with our previous studies, we wholly define the genetic interplay among the Aurora kinases and reinforce the importance of AURKA expression in oocyte meiosis.

Identification of Aurora A kinase allosteric inhibitors: A comprehensive virtual screening through fingerprint-based similarity search, molecular docking, machine learning and molecular dynamics simulation

The Aurora A kinase (AAK) protein controls spindle assembly and promotes cell divisions in various diseases including cancer. In the present study, allosteric inhibition of AAK protein through different advanced computational screening approaches is employed to target AAK’s allosteric inhibition-modulation. Precisely, extensive computational techniques including allosteric binding sites recognition of AAK protein, fingerprint-based similarity search, multi-step molecular docking through AutoDock Vina and PLANTS, and a 100 ns molecular dynamics (MD) simulations studies were carried out followed by the calculation of binding free energy with MM-GBSA based approaches, has been employed for identification of potential allosteric inhibitors-modulators of AAK protein. The study outcome highlighted that all three identified small molecular chemical entities exhibit strong binding interaction affinity in both the docking analyses at the allosteric domain of AAK protein and also greater interaction stability in comparison to the considered standard compound. In addition, all identified three screened hits also show acceptable pharmacokinetics and medicinal chemistry properties, which certainly dictates their potentiality for becoming good drug-like compounds for inhibiting-modulating the activity of AAK protein binds with similar amino acids of the allosteric domain of AAK protein with selected three compounds. All the selected molecules were found to show an acceptable ADMET profile. Moreover, the MM-GBSA-based binding energy was found to be in the range of −8 to −35 Kcal/mol, which showed a strong association between proposed molecules and AAK protein. Comprehensive computational approach shows that the selected proposed three inhibitors of AAK protein are the best candidates as potential inhibitors.