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Cancer is a devastating disease, but advancements in cancer treatment offer hope for the future. Aurora kinases are a family of serine/threonine kinases that play critical roles in cell cycle control and mitosis. There are three members of the Aurora kinase family in humans: Aurora-A kinase, Aurora-B kinase, and Aurora-C kinase. This study focuses on the synthesis of hybrid compounds combining adamantane and 1,3,4-oxadiazole as potential inhibitors of Aurora-A kinase. A series of novel 4-((5-((3r,5r,7r)-adamantan-1-yl)-1,3,4-oxadiazol-2-yl)thio)-N,N-2-yn-1-amine were synthesized and evaluated against Aurora-A kinase. The most potent derivatives were 6a and 6k with IC50 values 36.6 and 38.8 μM, respectively. Docking studies probed the binding interactions of these compounds within the active site of the kinase. The findings contribute to the development of novel cancer therapeutics and offer promise for more effective and targeted treatments in the future. [ABSTRACT FROM AUTHOR]

Abstract Introduction Aurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers. Objective To design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors. Method A total of 21 Pyrazole derivatives P (1–21) were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR, 1H NMR, 13C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay. Results The cytotoxicity assay (MTT assay) showed that compound P-6 exhibited potent cytotoxicity (IC50 = 0.37–0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. Compound P-6 also showed inhibition of Aurora-A kinase with an IC50 value of 0.11 ± 0.03 µM. A Docking study was done to compound P-6 and P-20 into the active site of Aurora A kinase, in order to get the probable binding model for further study. Conclusion A series of 21 novel pyrazole derivatives P(1–21) were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established that P-6 is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase.

Introduction: Aurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers. Objective: To design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors. Method: A total of 21 Pyrazole derivatives P (1–21) were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR, 1H NMR, 13C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay. Results: The cytotoxicity assay (MTT assay) showed that compound P-6 exhibited potent cytotoxicity (IC50 = 0.37–0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. Compound P-6 also showed inhibition of Aurora-A kinase with an IC50 value of 0.11 ± 0.03 µM. A Docking study was done to compound P-6 and P-20 into the active site of Aurora A kinase, in order to get the probable binding model for further study. Conclusion: A series of 21 novel pyrazole derivatives P(1–21) were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established that P-6 is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase. [ABSTRACT FROM AUTHOR]

Objective: To explore and study the repair effect of Aurora-A kinase on lung injury in rats with acute pancreatitis. Methods: 36 male SD rats were divided into three groups: control group, model group and Aurora-A group. The control group underwent sham operation, the model group was treated with the same amount of normal saline after the acute pancreatitis model was established, and the Aurora-A group was treated with the acute pancreatitis model and the mouse Aurora-A factor-MLN8054 10 mg/kg was injected into the dorsal penis. Treatment, record the repair of lung injury in rats. Results: No rats died during the modeling process. The lung tissue pathology scores, serum neutrophil elastase (NE), and myelopathy of the model group and the Aurora-A group 2 and 4 weeks after modeling The relative expression levels of myeloperoxidase (MPO), lung tissue W/D, lung tissue protein kinase B (AKT), and extracellular signal-regulated kinase 1 (ERK1) protein were all higher than those of the control group (P<0.05), Aurora -A group is less than the model group (P<0.05). Conclusion: The application of Aurora-A kinase in acute pancreatitis rats can inhibit the activation of Akt/ERK signaling pathway, reduce the expression of serum NE and MPO, and promote lung injury repair. [ABSTRACT FROM AUTHOR]

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Using N-Myc 61-89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N-Myc/Aurora-A protein-protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these - N-Myc 73-94-N85C/G89C-mal - is shown to favour a more Aurora-A compliant binding ensemble in comparison to the linear wild-type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora-A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora-A surface. Taken together this work unveils the first orthosteric N-Myc/Aurora-A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality., (© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

Different protein kinases control signaling emanating from the T cell receptor (TCR) during antigen-specific T cell activation. Mitotic kinases, e.g. Aurora-A, have been widely studied in the context of mitosis due to their role during microtubule (MT) nucleation, becoming critical regulators of cell cycle progression. We have recently described a specific role for Aurora-A kinase in antigenic T cell activation. Blockade of Aurora-A in T cells severely disrupts the dynamics of MTs and CD3ζ-bearing signaling vesicles during T cell activation. Furthermore, Aurora-A deletion impairs the activation of signaling molecules downstream of the TCR. Targeting Aurora-A disturbs the activation of Lck, which is one of the first signals that drive T cell activation in an antigen-dependent manner. This work describes possible models of regulation of Lck by Aurora-A during T cell activation. We also discuss possible roles for Aurora-A in other systems similar to the IS, and its putative functions in cell polarization. [ABSTRACT FROM AUTHOR]

Myc family proteins promote cancer by inducingwidespread changes in gene expression. Their rapid turnover by the ubiquitin--proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCFFbxW7. However, N-Myc protein (the product of the MYCN oncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A--selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxW7. We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxW7 to disfavor the generation of Lys48-linked polyubiquitin chains. [ABSTRACT FROM AUTHOR]

The Aurora are a conserved family of serine/threonine kinases with essential functions in cell division. In mitosis, Aurora kinases are required for chromosome segregation, condensation and orientation in the metaphase plate, spindle assembly, and the completion of cytokinesis. This review presents the Aurora kinases, their partners and how their interactions impact on the different mitotic functions.

Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. EGFR pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia-localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinib restrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities.

Human tumours exhibit a variety of genetic alterations, including point mutations, translocations, gene amplifications and deletions, as well as aneuploid chromosome numbers. For carcinomas, aneuploidy is associated with poor patient outcome for a large variety of tumour types, including breast, colon and renal cell carcinoma. The Renal cell cancer (RCC) is a heterogeneous carcinoma consisting of different histologic types. The clear renal cell carcinoma (ccRCC) is the most common subtype and represents 85 % of the RCC. Central to the biology of the ccRCC is the loss of function of the Von Hippel Lindau gene but is also associated with genetic instability that could be caused by abrogation of the cell cycle mitotic spindle checkpoint and may involve the Aurora kinases, which regulate centrosome maturation. Aneuploidy can also result from the loss of cell-cell adhesion and apical-basal cell polarity that also may be regulated by the mitotic kinases (Plk1, CK2, DLCK1 and Aurora kinases). In this review, we describe the non mitotic unconventional functions of these kinases in renal tumourigenesis.

Metastatic breast cancer, despite many medical advances, remains an incurable disease. Therefore, treatments that overcome cancer cell resistance to current treatments are needed to decrease relapse and onset of metastatic disease. Aurora-A kinase has been implicated in breast cancer tumorigenesis and progression of the disease. It has also been shown to play a role in increasing a more chemotherapy-resistant, mesenchymal phenotype, and cells with stem cell-like characteristics. Pre-clinical data have been encouraging with inhibitors of Aurora-A kinase signaling, showing decreased proliferation and increased sensitivity of breast cancer cells to both hormonal and chemotherapy treatments. In early clinical trials with Alisertib, the most clinically advanced Aurora-A inhibitor, there have been early signals of activity, especially in the HR+ and HER2-positive breast cancer patient population. There is ongoing research in developing further specific Aurora-A and pan-Aurora kinase inhibitors and to identify biomarkers to show appropriate patient population for treatment. The first breast cancer-specific clinical trial with an Alisertib and Fulvestrant combination has completed accrual, and we are eagerly awaiting data to confirm that Aurora-A kinase inhibition has a role in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Osteoprotegerin (OPG) is a glycoprotein that has multifaceted role and is associated with several cancer malignancies like that of bladder carcinoma, gastric carcinoma, prostate cancer, multiple myeloma and breast cancer. Also OPG has been associated with several organ pathologies. The widespread expression of OPG suggests that OPG may have multiple biological activities that are yet to be explored.Methods: The anchorage-independent sphere cultures of the adherent cells were instrumental in our study as it provided a deeper insight into the complexity of a 3D tumor. Cytokine profiling was performed for OPG's detection in the microenvironment. ELISA and western blotting were performed to quantify the OPG secretion and measure the protein levels respectively. OPG expression was detected in human breast cancer tissue samples by IHC. To decipher OPG's role in tumor aggressiveness both recombinant human OPG as well as OPG rich and depleted breast cancer cell conditioned media were tested. Western blotting and MTT assay were performed to detect changes in signaling pathways and proliferation that were induced in presence of OPG. Onset of aneuploidy, in presence of OPG, was measured by cell cycle analysis and western blotting. Finally, human Breast Cancer qBiomarker Copy Number PCR Array was used to detect how OPG remarkably induced gene copy numbers for oncogenic pathway regulators.Results: SUM149PT and SUM1315M02 cells secrete high levels of the cytokine OPG compared to primary human mammary epithelial cells (HMEC). High expression of OPG was also detected in human breast cancer tissue samples compared to the uninvolved tissue from the same patient. OPG induced proliferation of control HMEC spheres and triggered the onset of aneuploidy in HMEC sphere cultures. OPG induced the expression of aneuploidy related kinases Aurora-A Kinase (IAK-1), Bub1 and BubR1 probably through the receptor activator of nuclear factor kappa-B ligand (RANKL) and syndecan-1 receptors via the Erk, AKT and GSK3(3 signaling pathway. Gene copy numbers for oncogenic pathway regulators such AKT1, Aurora-A Kinase (AURKA or IAK-1), epidermal growth factor receptor (EGFR) and MYC with a reduction in the copy numbers of cyclin dependent kinase inhibitor 2A (CDKN2A), PTEN and DNA topoisomerase 2 alpha (TOP2A) were induced in presence of OPG.Conclusions: These results highlight the role of OPG in reprogramming normal mammary epithelial cells to a tumorigenic state and suggest promising avenues for treating inflammatory breast cancer as well as highly invasive breast cancer with new therapeutic targets. [ABSTRACT FROM AUTHOR]

The Aurora-kinase family comprises of cell cycle-regulated serine/threonine kinases playing a vital role during mitosis. Aurora-A kinase is involved in multiple mitotic events in cell cycle and is a major regulator of centrosome function during mitosis. Aurora-A is overexpressed in breast, lung, colon, ovarian, glial, and pancreatic cancer. Hence, Aurora-A kinase is a promising target in cancer therapy. In our current study, a four-point 3D QSAR pharmacophore model has been generated using substituted pyrimidine class of Aurora-A kinase inhibitors. It had a fixed cost value 88.7429. The model mapped well to the external test set comprising of clinically active molecules, with a correlation coefficient r  = 0.99. From the mapping, it was found that the hydrophobic features (HY) of a molecule play an important role for Aurora-A kinase inhibitory activity, whereas the ring aromatic feature provides geometric constraint for spatial alignment of different functional group. The hypothesis, with one hydrogen bond acceptor, two ring aromatic features, and one hydrophobic feature, was selected to screen miniMaybridge database. The screened ligands were filtered on the basis of activity, shape, and drug likeliness. This led to the identification of five top hits. These identified potential leads were further subjected to docking with the ATP-binding site of Aurora-A kinase. The molecular dynamic simulation studies of top lead molecules having diverse scaffolds endorsed that the identified molecules had distinctive ability to inhibit Aurora-A kinase. Thus, this study may facilitate the medicinal chemists to design promising ligands with various scaffolds to inhibit Aurora-A kinase. Communicated by Ramaswamy H. Sarma.

Human tumors exhibit a variety of genetic alterations, including point mutations, translocations, gene amplifications and deletions, as well as aneuploid chromosome numbers. For carcinomas, aneuploidy is associated with poor patient outcome for a large variety of tumor types, including breast, colon, and renal cell carcinoma. The Renal cell carcinoma (RCC) is a heterogeneous carcinoma consisting of different histologic types. The clear renal cell carcinoma (ccRCC) is the most common subtype and represents 85% of the RCC. Central to the biology of the ccRCC is the loss of function of the Von Hippel--Lindau gene, but is also associated with genetic instability that could be caused by abrogation of the cell cycle mitotic spindle checkpoint and may involve the Aurora kinases, which regulate centrosome maturation. Aneuploidy can also result from the loss of cell--cell adhesion and apical--basal cell polarity that also may be regulated by the mitotic kinases (polo-like kinase 1, casein kinase 2, doublecortin-like kinase 1, and Aurora kinases). In this review, we describe the "non-mitotic" unconventional functions of these kinases in renal tumorigenesis. [ABSTRACT FROM AUTHOR]

Aurora-A kinase (AURKA) overexpression in numerous tumors induces aneuploidy, in part because of cytokinetic defects. Alisertib and other small-molecule inhibitors targeting AURKA are effective in some patients as monotherapies or combination therapies. Epidermal growth factor receptor (EGFR) pro-proliferative signaling activity is commonly elevated in cancer, and the EGFR inhibitor erlotinib is commonly used as a standard of care agent for cancer. An erlotinib/alisertib combination therapy is currently under assessment in clinical trials, following pre-clinical studies that indicated synergy of these drugs in cancer. We were interested in further exploring the activity of this drug combination. Beyond well-established functions for AURKA in mitotic progression, additional non-mitotic AURKA functions include control of ciliary stability and calcium signaling. Interestingly, alisertib exacerbates the disease phenotype in mouse models for autosomal-dominant polycystic kidney disease (ADPKD), a common inherited syndrome induced by aberrant signaling from PKD1 and PKD2, cilia-localized proteins that have calcium channel activity. EGFR is also more active in ADPKD, making erlotinib also of potential interest in this disease setting. In this study, we have explored the interaction of alisertib and erlotinib in an ADPKD model. These experiments indicated erlotinibrestrained cystogenesis, opposing alisertib action. Erlotinib also interacted with alisertib to regulate proliferative signaling proteins, albeit in a complicated manner. Results suggest a nuanced role of AURKA signaling in different pathogenic conditions and inform the clinical use of AURKA inhibitors in cancer patients with comorbidities. [ABSTRACT FROM AUTHOR]

Aurora kinase family is a group of serine/threonine protein kinase. It is the main regulator in mitosis, including centrosome regulation, spindle formation, and chromosome separation. Aurora-A is an oncogene that is highly expressed in various human tumors, including osteosarcoma. Its high expression level and malignance and tumor metastasis are correlated. Aurora-A is a potential tumor marker. The progress of Aurora-A kinase in tumor research is summarized in this article. [ABSTRACT FROM AUTHOR]

Aurora-A, a centrosome-localized serine/threonine kinase, is over-expressed in multiple human cancers. We previously reported Zhang et al. (Biochem Biophys Res Commun , 357:347-352) intramolecular inhibitory regulation of Aurora-A between its N-terminal (Nt) regulatory domain (amino acids 1-128, Nt) and C-terminal catalytic domain (aa 129-403, Cd). Here, we identified two essential sites located on the Nt of Aurora-A (Lys 99 and Lys 119) and demonstrate that mutation of either residue to Gly could cause the Nt and C-terminal lobes of the catalytic domain in Aurora-A to form a closed conformation, resulting in a loss of kinase activity. This inactive conformation was reversed by adding C26 peptide (274-299) or Ajuba, which is a required activator of Aurora-A. Over-expression of either mutant induced G2/M arrest. These results provide a basis for future anti-cancer studies targeting Aurora-A. [ABSTRACT FROM AUTHOR]

Abstract: Pyrazole has been the topic of interest for thousands of researchers across the world because of its wide spectrum pharmacological activities. Various structural modifications of the pyrazole nucleus have been made to explore its characteristics and biological potential. The present work aims to review the use of molecular modeling in the designing of novel pyrazole analogs that may target various receptors such as protein kinase inhibitor, tyrosine kinase, Aurora-A kinase, tumor growth factor (TGF), cyclin dependent kinase (CDK) and fibroblast growth factor (FGF), which are significant for the management of cancer. An insight has been given in this article for the importance of pyrazoles in the treatment of cancer and the perspectives that they hold for future research. [Copyright &y& Elsevier]

Highlights: [•] AurA directly phosphorylates Drok in vitro. [•] AurA is required for eye morphogenesis and ring canal morphology. [•] One copy of sqhEE enhances aurA mutant phenotypes. [•] The nonphosphorylatable Droks show stronger effects than wild-type Drok. [•] Reduction of Myosin compensates the defects induced by the nonphosphorylatable Droks. [ABSTRACT FROM AUTHOR]

In this study, immunohistochemical expression of five proliferation markers: Ki-67, aurora-A kinase, survivin, B-Myb and cyclin B1, was analyzed. Consecutive 215 tumor samples from breast cancer patients operated from 2002 to 2003 were analyzed using the TMA ('tissue microarray') method. The median follow-up was 95 months (from 7.8 to 107 months). Statistically significant correlations between expression levels in five proliferation markers, and correlations between some of the proliferation markers and traditional prognostic factors were found. Statistically significant prognostic influence of aurora-A kinase, survivin and B-Myb expression levels on overall and disease-free survival was found, and cyclin B1 expression level on disease-free survival. A multivariate analysis confirmed survivin and B-Myb expression as independent prognostic factors of overall ( p = 0.0195; p = 0.0004) and disease-free survival ( p = 0.0107 and p = 0.0205) in breast cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: A series of N,1,3-triphenyl-1H-pyrazole-4-carboxamide derivatives have been designed, synthesized and evaluated for their potential antiproliferation activity and Aurora-A kinase inhibitory activity. Among all the compounds, compound 10e possessed the most potent biological activity against HCT116 and MCF-7 cell lines with IC50 values of 0.39±0.06μM and 0.46±0.04μM, respectively, which were comparable to the positive control. Compound 10e also exhibited significant Aurora-A kinase inhibitory activity (IC50 =0.16±0.03μM). Docking simulation was performed to position compound 10e into the active site of Aurora-A kinase, in order to get the probable binding model for further study. The results of Western-blot assay demonstrated that compound 10e possessed good Aurora-A kinase inhibitory activity against HCT116. Based on the preliminary results, it is deduced that compound 10e with potent Aurora-A kinase inhibitory activity may be a potential anticancer agent. [Copyright &y& Elsevier]

The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self-renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Two series of 3-aminopyrazole compounds including 24 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles and 16 pyrazolo[3,4-b]pyridines were synthesized and evaluated against HCT116, A549, and A2780 tumor cell lines. Among them, three compounds were found to have the ideal anti-proliferative activities in vitro. Docking experiments showed that the novel pyrazolo[3,4-b]pyridines share the similar interaction mode with Aurora-A kinase as PHA739358. [Copyright &y& Elsevier]

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules. [ABSTRACT FROM AUTHOR]

Aurora kinases are a family of cell division regulators that govern the correct assembly of a bipolar mitotic spindle and the fidelity of chromosome segregation. Their overexpression is associated with genomic instability and aneuploidy, and is frequently observed in cancer. Accordingly, competitive inhibitors targeting Aurora kinase activity at the ATP-binding site are being investigated for therapeutic purposes. Despite promising pre-clinical data, these molecules display moderate effects in clinical trials and incomplete selectivity, either against distinct family members, or other kinases. As an alternative approach, protein-protein interaction inhibitors targeting mitotic kinases and their activators can be exploited to achieve increased specificity of action. In this study, a virtual screening of small molecules led to the identification of 25 potential inhibitors of the interaction between Aurora-A and its activator TPX2. In vitro experiments confirmed that 4 hits bind Aurora-A in the low micromolar range and compete for TPX2 binding. Immunofluorescence assays showed that 2 compounds also yield lowered Aurora-A activity and spindle pole defects in cultured osteosarcoma cells. The identified protein-protein interaction inhibitors of the Aurora-A/TPX2 complex might represent lead compounds for further development towards pioneering anti-cancer drugs and provide the proof-of-concept for a new exploitable strategy to target mitotic kinases.

We have recently demonstrated that Aurora-A kinase is a potential oncogene to develop mammary gland tumors in mice, when expressed under MMTV promoter. These tumors contain phosphorylated forms of Akt and mTOR, suggesting that Akt-mTOR pathway is involved in transformed phenotype induced by Aurora-A. In the present studies, we discovered that stable cell lines expressing Aurora-A contain phosphorylation of Akt Ser473 after prolonged passages of cell culture, not in cells of the early period of cell culture. Levels of PTEN tumor suppressor are significantly reduced in these late passage cells at least in part due to increased poly ubiquitination of the protein. Akt-activated Aurora-A cells formed larger colonies in soft agar and are resistant to UV-induced apoptosis. Aurora-A inhibitor, VX-680, can cause cell death of Aurora-A cells in which Akt is not activated. siRNA-mediated depletion of mTOR in those cells resulted in decreased phosphorylation of Akt Ser473, suggesting that TORC2 complex phosphorylates Akt in Aurora-A cells. Treatment of late-passage Aurora-A cells with mTOR inhibitor reduced colony formation in soft agar. These results strongly suggest that commitment of cell transformation by Aurora-A is determined by at least co-activation of Akt/mTOR pathway.