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https://www.readbyqxmd.com/read/28819760/effect-of-alisertib-an-investigational-aurora-a-kinase-inhibitor-on-the-qtc-interval-in-patients-with-advanced-malignancies
#1
Xiaofei Zhou, John Nemunaitis, Shubham Pant, Todd M Bauer, Manish Patel, John Sarantopoulos, A Craig Lockhart, Daniel Goodman, Dirk Huebner, Diane R Mould, Karthik Venkatakrishnan
Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment...
August 18, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28818446/characterization-of-a-highly-selective-inhibitor-of-the-aurora-kinases
#2
Fleur M Ferguson, Zainab M Doctor, Apirat Chaikuad, Taebo Sim, Nam Doo Kim, Stefan Knapp, Nathanael S Gray
Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity...
August 10, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28808254/ikk2-regulates-cytokinesis-during-vertebrate-development
#3
Hongyuan Shen, Eun Myoung Shin, Serene Lee, Sinnakaruppan Mathavan, Hiromi Koh, Motomi Osato, Hyungwon Choi, Vinay Tergaonkar, Vladimir Korzh
NFκB signaling has a pivotal role in regulation of development, innate immunity, and inflammation. Ikk2 is one of the two critical kinases that regulate the NFκB signaling pathway. While the role of Ikk2 in immunity, inflammation and oncogenesis has received attention, an understanding of the role of Ikk2 in vertebrate development has been compounded by the embryonic lethality seen in mice lacking Ikk2. We find that despite abnormal angiogenesis in IKK2 zygotic mutants of zebrafish, the maternal activity of Ikk2 supports embryogenesis and maturation of fertile animals and allows to study the role of IKK2 in development...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28763871/-the-function-of-aurora-a-and-its-role-in-the-development-of-liver-cancer
#4
M Li, Z G Ren
Aurora A plays a key role in cellular mitosis. It is located in the centrosome and spindle, and is mainly involved in the processes of centrosome maturation and separation, bipolar spindle assembly, and the regulation of mitotic progression. Recent studies have suggested that Aurora A is involved in tumorigenesis and tumor development through multiple mechanisms. Overexpression of Aurora A could cause abnormal centrosome amplification, aneuploidy formation, and G2/M checkpoint defects, which result in chromosome instability and imbalance between cell division and apoptosis, and eventually leads to abnormal cell proliferation...
June 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28761362/targeted-tpx2-increases-chromosome-missegregation-and-suppresses-tumor-cell-growth-in-human-prostate-cancer
#5
Hung-Wei Pan, Hsing-Hao Su, Chao-Wen Hsu, Guan-Jin Huang, Tony Tong-Lin Wu
Prostate cancer is a complex disease that can be relatively harmless or extremely aggressive. Although androgen-deprivation therapy is a commonly used treatment for men with prostate cancer, the adverse effects can be detrimental to patient health and quality of life. Therefore, identifying new target genes for tumor growth will enable the development of novel therapeutic intervention. TPX2 plays a critical role in chromosome segregation machinery during mitosis. Low rates of chromosome missegregation can promote tumor development, whereas higher levels might promote cell death and suppress tumorigenesis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28748768/allosteric-targeting-of-aurora-a-kinase-using-small-molecules-a-step-forward-towards-next-generation-medicines
#6
Resmi C Panicker, Anthony G Coyne, Rajavel Srinivasan
Aurora A (AurA) kinase is a key mitotic protein essential for carrying out numerous cellular functions. Overexpression or malfunction of this enzyme results in numerous human diseases most notably in cancer. Several small molecule inhibitors targeting the ATP binding site of this enzyme are in various stages of clinical development. However, ATP binding site inhibitors can result in selectivity problems often leading to undesirable off-target effects. Moreover, these drugs are prone to drug resistance problem rendering them unfit for long-term administration...
July 27, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28745816/the-role-of-tacc3-in-mitotic-spindle-organization
#7
REVIEW
Zhi-Ming Ding, Chun-Jie Huang, Xiao-Fei Jiao, Di Wu, Li-Jun Huo
TACC3 regulates spindle organization during mitosis and also regulates centrosome-mediated microtubule nucleation by affecting γ-Tubulin ring complexes. In addition, it interacts with different proteins (such as ch-TOG, clathrin and Aurora-A) to function in mitotic spindle assembly and stability. By forming the TACC3/ch-TOG complex, TACC3 acts as a plus end-tracking protein to promote microtubule elongation. The TACC3/ch-TOG/clathrin complex is formed to stabilize kinetochore fibers by crosslinking adjacent microtubules...
July 26, 2017: Cytoskeleton
https://www.readbyqxmd.com/read/28733545/a-small-molecule-inhibitor-targeting-the-aurkc-i%C3%AE%C2%BAb%C3%AE-interaction-decreases-transformed-growth-of-mda-mb-231-breast-cancer-cells
#8
Eun Hee Han, Jin-Young Min, Shin-Ae Yoo, Sung-Joon Park, Yun-Jeong Choe, Hee Sub Yun, Zee-Won Lee, Sun Woo Jin, Hyung Gyun Kim, Hye Gwang Jeong, Hyun Kyoung Kim, Nam Doo Kim, Young-Ho Chung
The Aurora kinases, Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) or meiosis (AURKC). Several Aurora kinase inhibitors are being investigated as novel anticancer therapeutics. Recent studies demonstrated that AURKC activation contributes to breast cancer cell transformation. Therefore, AURKC is both a promising marker and therapeutic target for breast cancer; however, its signaling network has not been fully characterized...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28720575/hsp72-and-nek6-cooperate-to-cluster-amplified-centrosomes-in-cancer-cells
#9
Josephina Sampson, Laura O'Regan, Martin Js Dyer, Richard Bayliss, Andrew M Fry
Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28706138/a-potential-panel-of-two-long-non-coding-rna-signature-to-predict-recurrence-of-patients-with-laryngeal-cancer
#10
Zhigang Bai, Enhong Shi, Qiwei Wang, Zhouwei Dong, Ping Xu
Accumulating evidence has shown that aberrant lncRNA expression plays an oncogenic or tumor-suppressive role in the tumorigenesis of laryngeal cancer. However, the prognostic roles of lncRNAs in laryngeal cancer recurrence are still poorly understood. In this study, we obtained lncRNA expression profiles of 109 patients with laryngeal cancer by mining previously published gene expression microarray data from the Gene Expression Omnibus (GEO) and identified two lncRNAs associated with laryngeal cancer recurrence in the training dataset by using Cox regression analysis...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700980/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#11
Thuy-Vy Do, Jeff Hirst, Stephen Hyter, Katherine F Roby, Andrew K Godwin
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700101/dynamic-equilibrium-of-the-aurora%C3%A2-a-kinase-activation-loop-revealed-by-single-molecule-spectroscopy
#12
James A H Gilburt, Hajrah Sarkar, Peter Sheldrake, Julian Blagg, Liming Ying, Charlotte A Dodson
The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small-molecule inhibitors. By using single-molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora A kinase is in dynamic equilibrium between a DFG-in-like active T-loop conformation and a DFG-out-like inactive conformation, and have measured the rate constants of interconversion. Addition of the Aurora A activating protein TPX2 shifts the equilibrium towards an active T-loop conformation whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T-loop...
July 12, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28685608/what-s-new-in-small-cell-lung-cancer-extensive-disease-an-overview-on-advances-of-systemic-treatment-in-2016
#13
Andreas Seeber, Christoph Leitner, Kathrin Philipp-Abbrederis, Gilbert Spizzo, Florian Kocher
Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials...
July 2017: Future Oncology
https://www.readbyqxmd.com/read/28654908/apio-ee-9-is-a-novel-aurora-a-and-b-antagonist-that-suppresses-esophageal-cancer-growth-in-a-pdx-mouse-model
#14
Guoguo Jin, Ke Yao, Zhiping Guo, Zhenjiang Zhao, Kangdong Liu, Fangfang Liu, Hanyong Chen, Dhilli Rao Gorja, Kanamata Reddy, Ann M Bode, Ziming Dong, Zigang Dong
Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28638452/targeting-tpx2-suppresses-the-tumorigenesis-of-hepatocellular-carcinoma-cells-resulting-in-arrested-mitotic-phase-progression-and-increased-genomic-instability
#15
Chao-Wen Hsu, Yu-Chia Chen, Hsing-Hao Su, Guan-Jin Huang, Chih-Wen Shu, Tony Tong-Lin Wu, Hung-Wei Pan
Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28620032/a-moving-target-structure-and-disorder-in-pursuit-of-myc-inhibitors
#16
REVIEW
Richard Bayliss, Selena G Burgess, Eoin Leen, Mark W Richards
The Myc proteins comprise a family of ubiquitous regulators of gene expression implicated in over half of all human cancers. They interact with a large number of other proteins, such as transcription factors, chromatin-modifying enzymes and kinases. Remarkably, few of these interactions have been characterized structurally. This is at least in part due to the intrinsically disordered nature of Myc proteins, which adopt a defined conformation only in the presence of binding partners. Owing to this behaviour, crystallographic studies on Myc proteins have been limited to short fragments in complex with other proteins...
June 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28610844/overexpression-of-eif4f-components-in-meningiomas-and-suppression-of-meningioma-cell-growth-by-inhibiting-translation-initiation
#17
Janet L Oblinger, Sarah S Burns, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, A Douglas Kinghorn, D Bradley Welling, Long-Sheng Chang
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation...
June 10, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28601256/aurora-a-kinase-is-a-priority-pharmaceutical-target-for-the-treatment-of-cancers
#18
REVIEW
Arun Prasath Damodaran, Lucie Vaufrey, Olivia Gavard, Claude Prigent
Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials...
June 7, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28586053/hdac6-inhibition-suppresses-chondrosarcoma-by-restoring-the-expression-of-primary-cilia
#19
Wei Xiang, Fengjing Guo, Weiting Cheng, Jiaming Zhang, Junming Huang, Rui Wang, Zhongxi Ma, Kai Xu
Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6...
June 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28552528/peroxiredoxins-are-required-for-spindle-assembly-chromosome-organization-and-polarization-in-mouse-oocytes
#20
Hyuk-Joon Jeon, Yong Seok Park, Dong-Hyung Cho, Jae-Sung Kim, Eunji Kim, Ho Zoon Chae, Sang-Young Chun, Jeong Su Oh
Peroxiredoxins (Prxs) are highly conserved antioxidant enzymes and are implicated in multiple biological processes; however, their function in oocyte meiosis has not been studied. Here we show that inhibition of Prx I and II results in spindle defects, chromosome disorganization, and impaired polarization in mouse oocytes. Prx I was specifically localized at the spindle, whereas Prx II was enriched at the oocyte cortex and chromosomes. Inhibition of Prx activity with conoidin A disturbed assembly of the microtubule organizing center (MTOC) through Aurora A regulation, leading to defects in spindle formation...
May 25, 2017: Biochemical and Biophysical Research Communications
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