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Aurora kinase

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https://www.readbyqxmd.com/read/27922739/tyrosine-kinase-aurora-kinase-and-leucine-aminopeptidase-as-attractive-drug-targets-in-anticancer-therapy-characterisation-of-their-inhibitors
#1
Joanna Ziemska, Jolanta Solecka
Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies...
2016: Roczniki Państwowego Zakładu Higieny
https://www.readbyqxmd.com/read/27922680/identification-of-key-genes-induced-by-platelet-rich-plasma-in-human-dermal-papilla-cells-using-bioinformatics-methods
#2
Haiyan Shen, Hanxiao Cheng, Haihua Chen, Jufang Zhang
Dermal papilla cells (DPCs) are located at the base of hair follicles, and are known to induce hair follicle regeneration. Platelet-rich plasma (PRP) functions in hair follicle regeneration. To investigate the influence of PRP on DPCs, the present study analyzed RNA‑seq data of human hair dermal papilla cells (HHDPCs) that were treated or untreated by PRP. The data included in the RNA‑seq were from two normal and two treated HHDPC samples. Following identification by Cuffdiff software, differentially expressed genes (DEGs) underwent enrichment analyses, and protein-protein interaction networks were constructed using Cytoscape software...
December 6, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27910998/aurora-a-shines-on-t-cell-activation-through-the-regulation-of-lck
#3
Noelia Blas-Rus, Eugenio Bustos-Morán, Noa B Martín-Cófreces, Francisco Sánchez-Madrid
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...
December 2, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/27909956/docking-and-three-dimensional-quantitative-structure-activity-relationship-analyses-of-imidazole-and-thiazolidine-derivatives-as-aurora-a-kinase-inhibitors
#4
Chaeuk Im
Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0...
December 1, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27905678/a-phase-i-ii-trial-of-at9283-a-selective-inhibitor-of-aurora-kinase-in-children-with-relapsed-or-refractory-acute-leukemia-challenges-to-run-early-phase-clinical-trials-for-children-with-leukemia
#5
B Vormoor, G J Veal, M J Griffin, A V Boddy, J Irving, L Minto, M Case, U Banerji, K E Swales, J R Tall, A S Moore, M Toguchi, G Acton, K Dyer, C Schwab, C J Harrison, J D Grainger, D Lancaster, P Kearns, D Hargrave, J Vormoor
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies...
December 1, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/27895801/in-vitro-evaluation-of-a-combination-treatment-involving-anticancer-agents-and-an-aurora-kinase-b-inhibitor
#6
Senna Sakai, Hiroto Izumi, Yukiko Yoshiura, Yoshifumi Nakayama, Takahiro Yamaguchi, Yoshikazu Harada, Chiho Koi, Hiroyuki Kurata, Yasuo Morimoto
Aurora kinase B (AURKB) inhibitors are regarded as potential molecular-targeting drugs for cancer therapy. The present study evaluated the cytotoxic effect of a combination of AZD1152-hQPA, an AURKB inhibitor, and various anticancer agents on the HeLa human cervical cancer cell line, as well as its cisplatin-resistant equivalent HCP4 cell line. It was demonstrated that AZD1152-hQPA had an antagonistic effect on the cytotoxicity of cisplatin, etoposide and doxorubicin, but had a synergistic effect on that of all-trans-retinoic acid (ATRA), Am80 and TAC-101, when tested on HeLa cells...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27893412/molecular-mechanism-and-therapeutic-implications-of-selinexor-kpt-330-in-liposarcoma
#7
Manoj Garg, Deepika Kanojia, Anand Mayakonda, Jonathan W Said, Ngan B Doan, Wenwen Chien, Trivadi S Ganesan, Linda Shyue Huey Chuang, Nachiyappan Venkatachalam, Erkan Baloglu, Sharon Shacham, Michael Kauffman, H Phillip Koeffler
Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells...
November 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27887633/antitumor-activity-of-ty-011-against-gastric-cancer-by-inhibiting-aurora-a-aurora-b-and-vegfr2-kinases
#8
Wang Liu, Yu Lu, Xiaoping Chai, Xiao Liu, Tong Zhu, Xihan Wu, Yanfen Fang, Xuan Liu, Xiongwen Zhang
BACKGROUND: Overexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B) and angiogenic receptor tyrosine kinase (VEGFR2). METHODS: HTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities...
November 25, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27884697/3-cyano-6-5-methyl-3-pyrazoloamino-pyridines-part-2-a-dual-inhibitor-of-aurora-kinase-and-tubulin-polymerization
#9
Masahiko Morioka
A new class of a dual inhibitor of Aurora kinase and tubulin polymerization was created by introducing various substituted phenoxyethylamino or pyridyloxyethylamino groups to the 2-position of 3-cyano-4-methyl-6-(5-methyl-3-pyrazoloamino)-pyridine. Compound 3g exhibited Aurora kinase inhibition, excellent protein kinase selectivity to Aurora kinase in comparison with 66 other kinases, inhibition of phosphorylation of Ser10 of histone H3 as an Aurora kinase inhibitor, inhibition of tubulin polymerization in vitro, good cell membrane permeability, and a good PK profile...
December 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27881301/structure-of-the-mis12-complex-and-molecular-basis-of-its-interaction-with-cenp-c-at-human-kinetochores
#10
Arsen Petrovic, Jenny Keller, Yahui Liu, Katharina Overlack, Juliane John, Yoana N Dimitrova, Simon Jenni, Suzan van Gerwen, Patricia Stege, Sabine Wohlgemuth, Pascaline Rombaut, Franz Herzog, Stephen C Harrison, Ingrid R Vetter, Andrea Musacchio
Kinetochores, multisubunit protein assemblies, connect chromosomes to spindle microtubules to promote chromosome segregation. The 10-subunit KMN assembly (comprising KNL1, MIS12, and NDC80 complexes, designated KNL1C, MIS12C, and NDC80C) binds microtubules and regulates mitotic checkpoint function through NDC80C and KNL1C, respectively. MIS12C, on the other hand, connects the KMN to the chromosome-proximal domain of the kinetochore through a direct interaction with CENP-C. The structural basis for this crucial bridging function of MIS12C is unknown...
November 3, 2016: Cell
https://www.readbyqxmd.com/read/27879390/phosphorylation-of-map65-1-by-arabidopsis-aurora-kinases-is-required-for-efficient-cell-cycle-progression
#11
Joanna Boruc, Annika Weimer, Virginie Stoppin-Mellet, Evelien Mylle, Ken Kosetsu, Cesyen Cedeno, Michel Jaquinod, Maria Njo, Liesbeth De Milde, Peter Tompa, Nathalie Gonzalez, Dirk Inze, Tom Beeckman, Marylin Vantard, Daniel van Damme
Aurora kinases are key effectors of mitosis. Plant Auroras are functionally divided into two clades. The α Auroras (Aurora1 and Aurora2) associate with the spindle and the cell plate and are implicated in controlling formative divisions throughout plant development. The β Aurora (Aurora3) localizes to centromeres and likely functions in chromosome separation. In contrast to the wealth of data available on the role of Aurora in other kingdoms, knowledge on their function in plants is merely emerging. This is exemplified by the fact that only histone H3 and the plant homologue of TPX2 have been identified as Aurora substrates in plants...
November 22, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27871934/v-src-induced-nuclear-localization-of-yap-is-involved-in-multipolar-spindle-formation-in-tetraploid-cells
#12
Keiko Kakae, Masayoshi Ikeuchi, Takahisa Kuga, Youhei Saito, Naoto Yamaguchi, Yuji Nakayama
The protein-tyrosine kinase, c-Src, is involved in a variety of signaling events, including cell division. We have reported that v-Src, which is a mutant variant of the cellular proto-oncogene, c-Src, causes delocalization of Aurora B kinase, resulting in a furrow regression in cytokinesis and the generation of multinucleated cells. However, the effect of v-Src on mitotic spindle formation is unknown. Here we show that v-Src-expressing HCT116 and NIH3T3 cells undergo abnormal cell division, in which cells separate into more than two cells...
November 18, 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27866912/investigation-of-candidate-genes-for-osteoarthritis-based-on-gene-expression-profiles
#13
Shuanghai Dong, Tian Xia, Lei Wang, Qinghua Zhao, Jiwei Tian
OBJECTIVE: To explore the mechanism of osteoarthritis (OA) and provide valid biological information for further investigation. METHODS: Gene expression profile of GSE46750 was downloaded from Gene Expression Omnibus database. The Linear Models for Microarray Data (limma) package (Bioconductor project, http://www.bioconductor.org/packages/release/bioc/html/limma.html) was used to identify differentially expressed genes (DEGs) in inflamed OA samples. Gene Ontology function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis of DEGs were performed based on Database for Annotation, Visualization and Integrated Discovery data, and protein-protein interaction (PPI) network was constructed based on the Search Tool for the Retrieval of Interacting Genes/Proteins database...
November 17, 2016: Acta Orthopaedica et Traumatologica Turcica
https://www.readbyqxmd.com/read/27859890/phosphorylation-of-serine-148-in-giardia-lamblia-end-binding-1-protein-is-important-for-cell-division
#14
Juri Kim, Hye Yeon Lee, Kyu-Ho Lee, Soon-Jung Park
Giardia lamblia is a unicellular organism, showing a polarity with two nuclei and cytoskeletal structures. Accurate positioning of these organelles is essential for division of G. lamblia, which is poorly understood. G. lamblia end-binding 1 (GlEB1) protein and G. lamblia aurora kinase (GlAK) have been shown to modulate microtubule (MT) distribution during cytokinesis. A direct association between GlEB1 and GlAK was demonstrated. Like GlEB1, GlAK was also found at nuclear envelopes and median bodies of G. lamblia...
November 16, 2016: Journal of Eukaryotic Microbiology
https://www.readbyqxmd.com/read/27849008/ku70-serine-155-mediates-aurora-b-inhibition-and-activation-of-the-dna-damage-response
#15
Victoria L Fell, Elizabeth A Walden, Sarah M Hoffer, Stephanie R Rogers, Amelia S Aitken, Louisa M Salemi, Caroline Schild-Poulter
The Ku heterodimer (Ku70/Ku80) is the central DNA binding component of the classical non-homologous end joining (NHEJ) pathway that repairs DNA double-stranded breaks (DSBs), serving as the scaffold for the formation of the NHEJ complex. Here we show that Ku70 is phosphorylated on Serine 155 in response to DNA damage. Expression of Ku70 bearing a S155 phosphomimetic substitution (Ku70 S155D) in Ku70-deficient mouse embryonic fibroblasts (MEFs) triggered cell cycle arrest at multiple checkpoints and altered expression of several cell cycle regulators in absence of DNA damage...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27837025/structural-basis-of-n-myc-binding-by-aurora-a-and-its-destabilization-by-kinase-inhibitors
#16
Mark W Richards, Selena G Burgess, Evon Poon, Anne Carstensen, Martin Eilers, Louis Chesler, Richard Bayliss
Myc family proteins promote cancer by inducing widespread 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 SCF(FbxW7) 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 SCF(FbxW7) We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27836666/aurora-b-kinase-is-required-for-cell-cycle-progression-in-silkworm
#17
Xiaoxu Gang, Wenliang Qian, Tianlei Zhang, Xinxin Yang, Qingyou Xia, Daojun Cheng
Aurora B kinase, a member of serine/threonine kinase family, is the catalytic subunit of the chromosomal passenger complex and is essential for chromosome alignment, chromosome segregation, and cytokinesis during mitosis. Here, we cloned the full-length cDNA sequence of silkworm Aurora B (BmAurB) gene and predicted that BmAurB protein contains a conserved S_TKc domain. Phylogenetic analysis between BmAurB and other Aurora kinases indicates that Aurora kinases may have evolved after separation between mammalian and insect, and prior to radiation of either mammalian or insects...
November 9, 2016: Gene
https://www.readbyqxmd.com/read/27831827/mitotic-entry-the-interplay-between-cdk1-plk1-and-bora
#18
Alfonso Parrilla, Luca Cirillo, Yann Thomas, Monica Gotta, Lionel Pintard, Anna Santamaria
Polo-like kinase 1 (Plk1) is an important mitotic kinase that is crucial for entry into mitosis after recovery from DNA damage-induced cell cycle arrest. Plk1 activation is promoted by the conserved protein Bora (SPAT-1 in C. elegans), which stimulates the phosphorylation of a conserved residue in the activation loop by the Aurora A kinase. In a recent article published in Cell Reports, we show that the master mitotic kinase Cdk1 contributes to Plk1 activation through SPAT-1/Bora phosphorylation. We identified 3 conserved Sp/Tp residues that are located in the N-terminal, most conserved part, of SPAT-1/Bora...
November 10, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27824120/aurora-a-kinase-inhibitor-aki603-induces-cellular-senescence-in-chronic-myeloid-leukemia-cells-harboring-t315i-mutation
#19
Le-Xun Wang, Jun-Dan Wang, Jia-Jie Chen, Bing Long, Ling-Ling Liu, Xi-Xiang Tu, Yu Luo, Yuan Hu, Dong-Jun Lin, Gui Lu, Zi-Jie Long, Quentin Liu
The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27816996/alisertib-demonstrates-significant-antitumor-activity-in-bevacizumab-resistant-patient-derived-orthotopic-models-of-glioblastoma
#20
C Kurokawa, H Geekiyanage, C Allen, I Iankov, M Schroeder, B Carlson, K Bakken, J Sarkaria, J A Ecsedy, A D'Assoro, B Friday, E Galanis
Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC50s ranging between 30 and 95 nM...
November 5, 2016: Journal of Neuro-oncology
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