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https://www.readbyqxmd.com/read/29191061/the-identification-of-new-atad2-bromodomain-inhibitors-the-application-of-combined-ligand-and-structure-based-virtual-screening
#1
B Sepehri, R Ghavami
Ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches were used to identify new inhibitors for ATAD2 bromodomain. The LBVS approach was used to search 23,129,083 clean compounds to identify compounds similar to an active compound with reported pIC50 equal to 7.2. Based on LBVS results, 19 compounds were selected. To perform SBVS, by applying nine filters on 23,129,083 clean compounds, 1,057,060 compounds were selected. After performing SBVS on these selected compounds with idock software, 16 compounds with the lowest binding energies were selected...
December 1, 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29148850/atad2-in-cancer-a-pharmacologically-challenging-but-tractable-target
#2
Muzammal Hussain, Yang Zhou, Yu Song, H M Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2's bromodomain (BRD) may be a very challenging task. ATAD2's BRD has been predicted as a "difficult to drug" or "least druggable" target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding...
November 17, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29077715/protein-dynamics-and-structural-waters-in-bromodomains
#3
Xiaoxiao Zhang, Kai Chen, Yun-Dong Wu, Olaf Wiest
Bromodomains are epigenetic readers of acetylated lysines that are integral parts of histone tails. The 61 bromodomains in humans are structurally highly conserved but specifically bind to widely varying recognition motifs, suggesting that dynamic rather than static factors are responsible for recognition selectivity. To test this hypothesis, the dynamics of the binding sites and structural water molecules of four bromodomains (ATAD2, BAZ2B, BRD2(1) and CREBBP) representing four different subtypes is studied with 1 μs MD simulations using the RSFF2 force field...
2017: PloS One
https://www.readbyqxmd.com/read/29043777/isoform-selective-atad2-chemical-probe-with-novel-chemical-structure-and-unusual-mode-of-action
#4
Amaury E Fernández-Montalván, Markus Berger, Benno Kuropka, Seong Joo Koo, Volker Badock, Joerg Weiske, Vera Puetter, Simon J Holton, Detlef Stöckigt, Antonius Ter Laak, Paolo A Centrella, Matthew A Clark, Christoph E Dumelin, Eric A Sigel, Holly H Soutter, Dawn M Troast, Ying Zhang, John W Cuozzo, Anthony D Keefe, Didier Roche, Vincent Rodeschini, Apirat Chaikuad, Laura Díaz-Sáez, James M Bennett, Oleg Fedorov, Kilian V M Huber, Jan Hübner, Hilmar Weinmann, Ingo V Hartung, Mátyás Gorjánácz
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.
November 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28983993/synthesis-and-demonstration-of-the-biological-relevance-of-sp-3-rich-scaffolds-distantly-related-to-natural-product-frameworks
#5
Daniel J Foley, Philip G E Craven, Patrick M Collins, Richard G Doveston, Anthony Aimon, Romain Talon, Ian Churcher, Frank von Delft, Stephen P Marsden, Adam Nelson
The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp(3) -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks...
October 6, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28968711/spectrum-of-germline-mutations-in-smokers-and-non-smokers-in-brazilian-non-small-cell-lung-cancer-nsclc-patients
#6
Patrícia P Couto, Luciana Bastos-Rodrigues, Hagit Schayek, Flavia M Melo, Raony G C Lisboa, Debora M Miranda, Alyne Vilhena, Allen E Bale, Eitan Friedman, Luiz De Marco
Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform...
October 26, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28928828/screening-of-candidate-key-genes-associated-with-human-osteosarcoma-using-bioinformatics-analysis
#7
Kefeng Zhang, Jianwen Gao, Yong Ni
The aim of the present study was to identify the key genes associated with osteosarcoma (OS) using a bioinformatics approach. Microarray data (GSE36004) was downloaded from the Gene Expression Omnibus database, including 19 OS cell lines and 6 normal controls. Differentially expressed genes (DEGs) in the OS cell lines were identified using the Limma package, and differentially methylated regions were screened with methyAnalysis in R. Copy number analysis was performed and genes with copy number gains/losses were further screened using DNAcopy and cghMCR packages...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28862840/discovery-of-inhibitors-of-four-bromodomains-by-fragment-anchored-ligand-docking
#8
Jean-Rémy Marchand, Andrea Dalle Vedove, Graziano Lolli, Amedeo Caflisch
The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation...
October 23, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28798233/the-atad2-bromodomain-binds-different-acetylation-marks-on-the-histone-h4-in-similar-fuzzy-complexes
#9
Cassiano Langini, Amedeo Caflisch, Andreas Vitalis
Bromodomains are protein modules adopting conserved helix bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders...
October 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28763839/-expression-of-atad2-in-different-liver-lesions-and-its-clinical-significance
#10
F Liu, X Zhou, H H Ji, H Li, F G Xiang
Objective: To examine the expression of ATAD2 in different liver lesions and its clinical significance. Methods: ATAD2 expression in 60 hepatocellular carcinoma (HCC) surgical specimens (49 of which have concurrent liver cirrhosis), 43 HCC biopsy specimens, 2 high-grade liver dysplastic nodule specimens, 3 low-grade liver dysplastic nodule specimens, 50 liver cirrhosis tissue samples, and 20 normal liver tissue samples were measured using immunohistochemistry. The F-test, q-test, t-test, and chi-square test were used for statistical analysis of data...
May 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28591577/androgen-receptor-deregulation-drives-bromodomain-mediated-chromatin-alterations-in-prostate-cancer
#11
Alfonso Urbanucci, Stefan J Barfeld, Ville Kytölä, Harri M Itkonen, Ilsa M Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R Jeffrey Karnes, Ashley E Ross, Edward M Schaeffer, Donald J Vander Griend, Stefan Knapp, Eva Corey, Felix Y Feng, Peter S Nelson, Fahri Saatcioglu, Karen E Knudsen, Teuvo L J Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G Mills
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect...
June 6, 2017: Cell Reports
https://www.readbyqxmd.com/read/28500727/biological-function-and-histone-recognition-of-family-iv-bromodomain-containing-proteins
#12
REVIEW
Jonathan T Lloyd, Karen C Glass
Bromodomain proteins function as epigenetic readers that recognize acetylated histone tails to facilitate the transcription of target genes. There are approximately 60 known human bromodomains, which are divided into eight sub-families based on structural conservation. The bromodomain-containing proteins in family IV include seven members (BRPF1, BRPF2, BRPF3, BRD7, BRD9, ATAD2, and ATAD2b). The bromodomains of each of these proteins recognize and bind acetyllysine residues on histone tails protruding from the nucleosome...
May 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28456593/the-role-of-mir-372-in-ovarian-carcinoma-cell-proliferation
#13
Xue Guan, Zhi-Hong Zong, Shuo Chen, Xiu-Bo Sang, Dan-Dan Wu, Li-Li Wang, Yao Liu, Yang Zhao
OBJECTIVES: MicroRNA-372 has been shown to be associated with multiple tumors' development and progression, by regulating the expression of proteins involved in cell cycle and apoptosis. However, the specific mechanism and function of miR-372 in ovarian carcinoma are not clear. Our study explored the role of miR-372 in ovarian carcinoma cell cycle and proliferation. MATERIALS AND METHODS: MiR-372 expression was quantified in normal ovarian tissue, benign tumors, primary ovarian carcinomas and metastatic omentum by qRT-PCR...
August 15, 2017: Gene
https://www.readbyqxmd.com/read/28415780/long-noncoding-rna-pcat-14-induces-proliferation-and-invasion-by-hepatocellular-carcinoma-cells-by-inducing-methylation-of-mir-372
#14
Yawei Wang, Ye Hu, Gang Wu, Ye Yang, Yanqing Tang, Wanchuan Zhang, Kaiyu Wang, Yu Liu, Xin Wang, Tiemin Li
Long non-coding RNAs (lncRNAs) regulate oncogenesis by inducing methylation of CpG islands to silence target genes. Here we show that the lncRNA PCAT-14 is overexpressed in patients with hepatocellular carcinoma (HCC), and is associated with a poor prognosis after surgery. Our results demonstrate that PCAT-14 promotes proliferation, invasion, and cell cycle arrest in HCC cells. In addition, PCAT-14 inhibits miR-372 expression by inducing methylation of the miR-372 promoter. Simultaneously, miR-372 eliminates the effects of PCAT-14 on proliferation, invasion, and cell cycle in HCC cells...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28069330/top2a-hells-atad2-and-tet3-are-novel-prognostic-markers-in-renal-cell-carcinoma
#15
Dong Chen, Matthias Maruschke, Oliver Hakenberg, Wolfgang Zimmermann, Christian G Stief, Alexander Buchner
OBJECTIVE: To identify and validate novel prognostic marker genes in clear cell renal cell carcinoma (RCC) that are increasingly expressed during tumor progression. METHODS: Total RNA was isolated from normal renal tissue, primary G1 and G3 tumors, 14 samples each, and 32 metastases from RCC patients. Expression profiles were created using oligonucleotide microarrays. Significant gene expression differences (P < .05) were identified among normal kidney, primary tumor, and metastases...
January 6, 2017: Urology
https://www.readbyqxmd.com/read/27895739/gene-expression-profiling-of-the-8q22-24-position-in-human-breast-cancer-tspyl5-mtdh-atad2-and-ccne2-genes-are-implicated-in-oncogenesis-while-wisp1-and-ext1-genes-may-predict-a-risk-of-metastasis
#16
Afsoon Taghavi, Mohammad Esmaeil Akbari, Mohammad Hashemi-Bahremani, Nahid Nafissi, Ahad Khalilnezhad, Seyed Mohammad Poorhosseini, Feyzollah Hashemi-Gorji, Vahid Reza Yassaee
Gene expression profiling has been suggested to predict breast cancer outcome. The prognostic value of the 8q22-24 position in breast cancer remains to be elucidated. The present study evaluated expression patterns of the genes located at this position in metastatic and non-metastatic breast cancer. A total of 85 patients with recurrent/metastatic (n=15) and non-metastatic (n=70) early-stage, estrogen receptor-positive and lymph node-negative breast tumors were included. In addition, 15 normal breast tissue samples were used as controls...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27612420/atad2-is-an-epigenetic-reader-of-newly-synthesized-histone-marks-during-dna-replication
#17
Seong Joo Koo, Amaury E Fernández-Montalván, Volker Badock, Christopher J Ott, Simon J Holton, Oliver von Ahsen, Joern Toedling, Sarah Vittori, James E Bradner, Mátyás Gorjánácz
ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27565325/microrna-520f-suppresses-growth-of-gastric-carcinoma-cells-by-target-atpase-family-aaa-domain-containing-protein-2-atad2
#18
S Hong, M Bi, S Chen, P Zhao, B Li, D Sun, J Tai
MicroRNAs (miRNAs) are small, non-coding RNAs that can serve as tumor suppressor genes or oncogenes in tumorigenesis. More and more evidence demonstrate that abnormal expression of miRNAs lead to the gastric carcinoma occurrence. In the present study, we revealed that the expression levels of miR-520f were significantly down-regulated in gastric carcinoma cells and clinical gastric carcinoma samples. Next, we demonstrated that introduction of miR-520f inhibited the growth of gastric carcinoma cells in vitro...
2016: Neoplasma
https://www.readbyqxmd.com/read/27565322/silencing-of-atpase-family-aaa-domain-containing-protein-2-inhibits-migration-and-invasion-of-colorectal-cancer-cells
#19
S Hong, M Bi, Z Yan, D Sun, L Ling, C Zhao
Colorectal cancer is one of the most common malignant tumors with a high rate of distant metastasis, postoperative recurrence and mortality. ATPase family AAA domain-containing protein 2 (ATAD2), a member of ATPase family, is highly expressed in various cancers, including colorectal cancer. However, whether ATAD2 plays a role in the migration and invasion of colorectal cancer cells remains unknown. In this study, we established ATAD2 knockdown in colorectal cancer cell lines by RNA interference and found that silencing of ATAD2 inhibited the migration and invasion ability of Caco-2 and SW-480 cells...
2016: Neoplasma
https://www.readbyqxmd.com/read/27530368/a-chemical-probe-for-the-atad2-bromodomain
#20
Paul Bamborough, Chun-Wa Chung, Emmanuel H Demont, Rebecca C Furze, Andrew J Bannister, Ka Hing Che, Hawa Diallo, Clement Douault, Paola Grandi, Tony Kouzarides, Anne-Marie Michon, Darren J Mitchell, Rab K Prinjha, Christina Rau, Samuel Robson, Robert J Sheppard, Richard Upton, Robert J Watson
ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
September 12, 2016: Angewandte Chemie
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