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https://www.readbyqxmd.com/read/29024811/cnot2-promotes-proliferation-and-angiogenesis-via-vegf-signaling-in-mda-mb-231-breast-cancer-cells
#1
Eun Jung Sohn, Deok-Beom Jung, HyoJung Lee, In Han, Jihyun Lee, Hyemin Lee, Sung-Hoon Kim
Here the underlying role of CNOT2, a subunit of CCR4-NOT complex, was elucidated in cancer progression. CNOT2 was overexpressed in HIT-T15, ASPC-1, BXPC-3, PC-3, LNCaP, MCF-7 and MDA-MB-231 cell lines, which was confirmed by Tissue array in various human tumor tissues. Also, CNOT2 depletion suppressed proliferation and colony formation of MDA-MB-231 cells. Of note, microarray revealed decreased expression of CNOT2, VEGF-A, HIF2 alpha (<0.5 fold) and increased expression of UMOD1, LOC727847, MMP4, hCG and other genes (>2...
October 9, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28992456/prediction-of-new-chromene-based-inhibitors-of-tubulin-using-structure-based-virtual-screening-and-molecular-dynamics-simulation-methods
#2
Hassan Aryapour, Maryam Dehdab, Farzin Sohraby, Afshar Bargahi
Multidrug resistance (MDR) is one of the serious problems in cancer research that causes failure in chemotherapy. Chromene-based compounds have been proven to be the novel anti-MDR agents for inhibiting proliferation of tumor cells through tubulin polymerization inhibition of by binding at the colchicine binding site. In this study, we screened a chromene-based database of small molecules using physicochemical, ADMET properties and molecular docking to identify potential hit compounds. In order to validate our hit compounds, molecular dynamics simulations and related analysis were carried out and the results suggest that our hit compounds (PubChem CIDs: 16814409, 17594471, 57367244 and 69899719) can prove to be potential inhibitors of tubulin...
September 27, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28978045/mitoriboscins-mitochondrial-based-therapeutics-targeting-cancer-stem-cells-cscs-bacteria-and-pathogenic-yeast
#3
Bela Ozsvari, Marco Fiorillo, Gloria Bonuccelli, Anna Rita Cappello, Luca Frattaruolo, Federica Sotgia, Rachel Trowbridge, Richard Foster, Michael P Lisanti
The "endo-symbiotic theory of mitochondrial evolution" states that mitochondrial organelles evolved from engulfed aerobic bacteria, after millions of years of symbiosis and adaptation. Here, we have exploited this premise to design new antibiotics and novel anti-cancer therapies, using a convergent approach. First, virtual high-throughput screening (vHTS) and computational chemistry were used to identify novel compounds binding to the 3D structure of the mammalian mitochondrial ribosome. The resulting library of ∼880 compounds was then subjected to phenotypic drug screening on human cancer cells, to identify which compounds functionally induce ATP-depletion, which is characteristic of mitochondrial inhibition...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28978032/vitamin-c-and-doxycycline-a-synthetic-lethal-combination-therapy-targeting-metabolic-flexibility-in-cancer-stem-cells-cscs
#4
Ernestina Marianna De Francesco, Gloria Bonuccelli, Marcello Maggiolini, Federica Sotgia, Michael P Lisanti
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28974240/association-of-a-novel-point-mutation-in-msh2-gene-with-familial-multiple-primary-cancers
#5
Hai Hu, Hong Li, Feng Jiao, Ting Han, Meng Zhuo, Jiujie Cui, Yixue Li, Liwei Wang
BACKGROUND: Multiple primary cancers (MPC) have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues...
October 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28967196/tetrazole-based-probes-for-integrated-phenotypic-screening-affinity-based-proteome-profiling-and-sensitive-detection-of-a-cancer-biomarker
#6
Zhengqiu Li, Ke Cheng, Jun-Seok Lee, Shao Q Yao, Ke Ding
Phenotypic screening has been a powerful approach in drug discovery, however it is hindered by difficulties in identifying the underlying cellular targets. To address this challenge, we have combined phenotypic screening of a fully functionalized small-molecule library with competitive affinity-based proteome profiling to map and functionally characterize the targets of screening hits. Using this approach, we identified ANXA2, PDIA3/4, FLAD1 and NOS2 as primary cellular targets of two bioactive molecules that inhibit cancer cell proliferation...
October 1, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28965432/novel-hdac8-inhibitors-a-multi-computational-approach
#7
M Manal, K Manish, D Sanal, A Selvaraj, V Devadasan, M J N Chandrasekar
Abnormal HDAC function triggers irregular gene transcription that hampers the essential cellular activities leading to tumour activation and progression. HDAC inhibition has, therefore, been reported as a potential target for cancer treatment. In the present study, a sequential computational framework was carried out to discover newer lead compounds, namely HDAC8 inhibitors for cancer therapy. Pharmacophoric hypotheses were generated based on hydroxamic acid derivatives reported earlier for HDAC inhibition...
September 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/28958848/sirt6-inhibitors-with-salicylate-like-structure-show-immunosuppressive-and-chemosensitizing-effects
#8
Patrizia Damonte, Giovanna Sociali, Marco Daniele Parenti, Debora Soncini, Inga Bauer, Silvia Boero, Alessia Grozio, Maria von Holtey, Francesco Piacente, Pamela Becherini, Roberta Sanguineti, Annalisa Salis, Gianluca Damonte, Michele Cea, Maximilien Murone, Alessandro Poggi, Alessio Nencioni, Alberto Del Rio, Santina Bruzzone
The NAD(+)-dependent deacetylase SIRT6 is an emerging cancer drug target, whose inhibition sensitizes cancer cells to chemo-radiotherapy and has pro-differentiating effects. Here we report on the identification of novel SIRT6 inhibitors with a salicylate-based structure. The new SIRT6 inhibitors show improved potency and specificity compared to the hit inhibitor identified in an in silico compound screen. As predicted based on SIRT6 biological roles, the new leads increase histone 3 lysine 9 acetylation and glucose uptake in cultured cells, while blocking TNF-α production and T lymphocyte proliferation...
September 19, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28957646/a-high-throughput-dose-response-cellular-thermal-shift-assay-for-rapid-screening-of-drug-target-engagement-in-living-cells-exemplified-using-smyd3-and-ido1
#9
Dean E McNulty, William G Bonnette, Hongwei Qi, Liping Wang, Thau F Ho, Anna Waszkiewicz, Lorena A Kallal, Raman P Nagarajan, Melissa Stern, Amy M Quinn, Caretha L Creasy, Dai-Shi Su, Alan P Graves, Roland S Annan, Sharon M Sweitzer, Marc A Holbert
A persistent problem in early small-molecule drug discovery is the frequent lack of rank-order correlation between biochemical potencies derived from initial screens using purified proteins and the diminished potency and efficacy observed in subsequent disease-relevant cellular phenotypic assays. The introduction of the cellular thermal shift assay (CETSA) has bridged this gap by enabling assessment of drug target engagement directly in live cells based on ligand-induced changes in protein thermal stability...
September 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28945760/appraising-the-relevance-of-dna-copy-number-loss-and-gain-in-prostate-cancer-using-whole-genome-dna-sequence-data
#10
Niedzica Camacho, Peter Van Loo, Sandra Edwards, Jonathan D Kay, Lucy Matthews, Kerstin Haase, Jeremy Clark, Nening Dennis, Sarah Thomas, Barbara Kremeyer, Jorge Zamora, Adam P Butler, Gunes Gundem, Sue Merson, Hayley Luxton, Steve Hawkins, Mohammed Ghori, Luke Marsden, Adam Lambert, Katalin Karaszi, Gill Pelvender, Charlie E Massie, Zsofia Kote-Jarai, Keiran Raine, David Jones, William J Howat, Steven Hazell, Naomi Livni, Cyril Fisher, Christopher Ogden, Pardeep Kumar, Alan Thompson, David Nicol, Erik Mayer, Tim Dudderidge, Yongwei Yu, Hongwei Zhang, Nimish C Shah, Vincent J Gnanapragasam, William Isaacs, Tapio Visakorpi, Freddie Hamdy, Dan Berney, Clare Verrill, Anne Y Warren, David C Wedge, Andrew G Lynch, Christopher S Foster, Yong Jie Lu, G Steven Bova, Hayley C Whitaker, Ultan McDermott, David E Neal, Rosalind Eeles, Colin S Cooper, Daniel S Brewer
A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12...
September 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28945333/targeting-the-hemopexin-like-domain-of-latent-matrix-metalloproteinase-9-prommp-9-with-a-small-molecule-inhibitor-prevents-the-formation-of-focal-adhesion-junctions
#11
Vincent M Alford, Anushree Kamath, Xiaodong Ren, Kunal Kumar, Qianwen Gan, Monaf Awwa, Michael Tong, Markus A Seeliger, Jian Cao, Iwao Ojima, Nicole S Sampson
A lack of target specificity has greatly hindered the success of inhibitor development against matrix metalloproteinases (MMPs) for the treatment of various cancers. The MMP catalytic domains are highly conserved, whereas the hemopexin-like domains of MMPs are unique to each family member. The hemopexin-like domain of MMP-9 enhances cancer cell migration through self-interaction and heterointeractions with cell surface proteins including CD44 and α4β1 integrin. These interactions activate EGFR-MAP kinase dependent signaling that leads to cell migration...
October 10, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28942113/novel-serms-based-on-3-aryl-4-aryloxy-2h-chromen-2-one-skeleton-a-possible-way-to-dual-er%C3%AE-vegfr-2-ligands-for-treatment-of-breast-cancer
#12
Guoshun Luo, Xinyu Li, Guoqing Zhang, Chengzhe Wu, Zhengpu Tang, Linyi Liu, Qidong You, Hua Xiang
There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective estrogen receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent estrogen receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors...
September 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28939880/the-number-of-key-carcinogenic-events-can-be-predicted-from-cancer-incidence
#13
Aleksey V Belikov
The widely accepted multiple-hit hypothesis of carcinogenesis states that cancers arise after several successive events. However, no consensus has been reached on the quantity and nature of these events, although "driver" mutations or epimutations are considered the most probable candidates. By using the largest publicly available cancer incidence statistics (20 million cases), I show that incidence of 20 most prevalent cancer types in relation to patients' age closely follows the Erlang probability distribution (R(2) = 0...
September 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28939121/discovery-of-novel-1-2-4-triazolo-4-3-a-quinoxaline-aminophenyl-derivatives-as-bet-inhibitors-for-cancer-treatment
#14
Imran Ali, Jooyun Lee, Areum Go, Gildon Choi, Kwangho Lee
Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay...
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28931883/high-throughput-targeted-screening-in-triple-negative-breast-cancer-cells-identifies-wnt-inhibiting-activities-in-pacific-brittle-stars
#15
Artem Blagodatski, Vsevolod Cherepanov, Alexey Koval, Vladimir I Kharlamenko, Yuri S Khotimchenko, Vladimir L Katanaev
Pro-proliferative oncogenic signaling is one of the hallmarks of cancer. Specific targeting of such signaling pathways is one of the main approaches to modern anti-cancer drug discovery, as opposed to more traditional search for general cytotoxic agents. Natural products, especially from marine sources, represent a largely untapped source of chemical diversity, which so far have mostly been screened for cytotoxicity. Here we present a pioneering pipeline of high-throughput screening of marine-based activities targeted against the Wnt signaling pathway, which is one of the key factors in oncogenic transformation, growth and metastasis in different cancers, including the devastating triple-negative breast cancer (TNBC) currently lacking any targeted therapies...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930221/compounds-from-terminalia-mantaly-l-combretaceae-stem-bark-exhibit-potent-inhibition-against-some-pathogenic-yeasts-and-enzymes-of-metabolic-significance
#16
Marthe Aimée Tchuente Tchuenmogne, Thierry Ngouana Kammalac, Sebastian Gohlke, Rufin Marie Toghueo Kouipou, Abdulselam Aslan, Muslum Kuzu, Veysel Comakli, Ramazan Demirdag, Silvère Augustin Ngouela, Etienne Tsamo, Norbert Sewald, Bruno Ndjakou Lenta, Fabrice Fekam Boyom
Background: Pathogenic yeasts resistance to current drugs emphasizes the need for new, safe, and cost-effective drugs. Also, new inhibitors are needed to control the effects of enzymes that are implicated in metabolic dysfunctions such as cancer, obesity, and epilepsy. Methods: The anti-yeast extract from Terminalia mantaly (Combretaceae) was fractionated and the structures of the isolated compounds established by means of spectroscopic analysis and comparison with literature data. Activity was assessed against Candida albicans, C...
January 24, 2017: Medicines (Basel, Switzerland)
https://www.readbyqxmd.com/read/28929756/fragment-based-discovery-and-optimization-of-enzyme-inhibitors-by-docking-of-commercial-chemical-space
#17
Axel Rudling, Robert Gustafsson, Ingrid Almlöf, Evert Homan, Martin Scobie, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark, Jens Carlsson
Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28927269/discovery-of-tamoxifen-and-n-desmethyl-tamoxifen-protein-targets-in-mcf-7-cells-using-large-scale-protein-folding-and-stability-measurements
#18
Ryenne N Ogburn, Lorrain Jin, He Meng, Michael C Fitzgerald
The proteins in an MCF-7 cell line were probed for tamoxifen (TAM) and n-desmethyl tamoxifen (NDT) induced stability changes using the Stability of Proteins from Rates of Oxidation (SPROX) technique in combination with two different quantitative proteomics strategies, including one based on SILAC and one based on isobaric mass tags. Over 1000 proteins were assayed for TAM- and NDT-induced protein stability changes, and a total of 163 and 200 protein hits were identified in the TAM and NDT studies, respectively...
October 11, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28926955/identification-of-novel-bisbenzimidazole-derivatives-as-anticancer-vacuolar-h%C3%A2-%C2%BA-atpase-inhibitors
#19
Renukadevi Patil, Arpita Kulshrestha, Anjali Tikoo, Sara Fleetwood, Gajendra Katara, Bala Kolli, William Seibel, Alice Gilman-Sachs, Shivaputra A Patil, Kenneth D Beaman
The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I-IV)...
September 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28925395/small-molecules-targeted-to-the-microtubule-hec1-interaction-inhibit-cancer-cell-growth-through-microtubule-stabilization
#20
M Ferrara, G Sessa, M Fiore, F Bernard, I A Asteriti, E Cundari, G Colotti, S Ferla, M Desideri, S Buglioni, D Trisciuoglio, D Del Bufalo, A Brancale, F Degrassi
Highly expressed in cancer protein 1 (Hec1) is a subunit of the kinetochore (KT)-associated Ndc80 complex, which ensures proper segregation of sister chromatids at mitosis by mediating the interaction between KTs and microtubules (MTs). HEC1 mRNA and protein are highly expressed in many malignancies as part of a signature of chromosome instability. These properties render Hec1 a promising molecular target for developing therapeutic drugs that exert their anticancer activities by producing massive chromosome aneuploidy...
September 18, 2017: Oncogene
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