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https://www.readbyqxmd.com/read/29456101/ligand-based-modeling-of-akt3-lead-to-potent-dual-akt1-akt3-inhibitor
#1
Mahmoud A Al-Sha'er, Mutasem O Taha
Akt1 and Akt3 are important serine/threonine-specific protein kinases involved in G2 phase required by cancer cells to maintain cell cycle and to prevent cell death. Accordingly, inhibitors of these kinases should have potent anti-cancer properties. This prompted us to use pharmacophore/QSAR modeling to identify optimal binding models and physicochemical descriptors that explain bioactivity variation within a set of 74 diverse Akt3 inhibitors. Two successful orthogonal pharmacophores were identified and further validated using receiver operating characteristic (ROC) curve analyses...
February 13, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29455836/the-rigidins-isolation-bioactivity-and-total-synthesis-novel-pyrrolo-2-3-d-pyrimidine-analogues-using-multicomponent-reactions
#2
Aletta E van der Westhuyzen, Liliya V Frolova, Alexander Kornienko, Willem A L van Otterlo
Rigidins (2-6) are pyrrolopyrimidine alkaloids isolated from marine tunicates. Since their isolation, refinement of their total syntheses, and biochemical evaluation, interest toward this pyrrolo[2,3-d]pyrimidine scaffold as a medicinal candidate has been triggered. The derivatization of these natural products has led to the discovery of a novel range of 7-deazahypoxanthines, which exhibit extremely potent anticancer activity in human cancer cell lines. A major breakthrough toward the synthesis of rigidin and various rigidin analogues has been the application of multicomponent reactions (MCRs)...
2018: Alkaloids. Chemistry and Biology
https://www.readbyqxmd.com/read/29454290/ligand-based-computer-aided-drug-design-reveals-new-tropomycin-receptor-kinase-a-trka-inhibitors
#3
Rand Shahin, Iman Mansi, Lubna Swellmeen, Tahani Alwidyan, Nabil Al-Hashimi, Yaser Al-Qarar'h, Omar Shaheen
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity...
January 13, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29452344/overexpression-of-blm-promotes-dna-damage-and-increased-sensitivity-to-platinum-salts-in-triple-negative-breast-and-serous-ovarian-cancers
#4
N J Birkbak, Y Li, S Pathania, A Greene-Colozzi, M Dreze, C Bowman-Colin, Z Sztupinszki, M Krzystanek, M Diossy, N Tung, P D Ryan, J E Garber, D P Silver, J D Iglehart, Z C Wang, D Szuts, Z Szallasi, A L Richardson
Background: Platinum based therapy is an effective treatment for a subset of triple negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared to resistant triple negative breast cancers in two independent neoadjuvant cisplatin treated cohorts...
February 14, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29447149/optimizing-homeostatic-cell-renewal-in-hierarchical-tissues
#5
Cesar Alvarado, Nicole A Fider, Helen J Wearing, Natalia L Komarova
In order to maintain homeostasis, mature cells removed from the top compartment of hierarchical tissues have to be replenished by means of differentiation and self-renewal events happening in the more primitive compartments. As each cell division is associated with a risk of mutation, cell division patterns have to be optimized, in order to minimize or delay the risk of malignancy generation. Here we study this optimization problem, focusing on the role of division tree length, that is, the number of layers of cells activated in response to the loss of terminally differentiated cells, which is related to the balance between differentiation and self-renewal events in the compartments...
February 15, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29443386/technical-note-error-metrics-for-estimating-the-accuracy-of-needle-instrument-placement-during-transperineal-mr-us-guided-prostate-interventions
#6
Ester Bonmati, Yipeng Hu, Barbara Villarini, Rachael Rodell, Paul Martin, Lianghao Han, Ian Donaldson, Hashim U Ahmed, Caroline M Moore, Mark Emberton, Dean C Barratt
PURPOSE: Image-guided systems that fuse magnetic resonance imaging (MRI) with three-dimensional (3D) ultrasound (US) images for performing targeted prostate needle biopsy and minimally-invasive treatments for prostate cancer are of increasing clinical interest. To date, a wide range of different accuracy estimation procedures and error metrics have been reported, which makes comparing the performance of different systems difficult. METHODS: A set of 9 measures are presented to assess the accuracy of MRI-US image registration, needle positioning, needle guidance, and overall system error, with the aim of providing a methodology for estimating the accuracy of instrument placement using a MR/US-guided transperineal approach...
February 14, 2018: Medical Physics
https://www.readbyqxmd.com/read/29441980/computational-prediction-of-new-cyp17-inhibitors-based-on-pharmacophore-modeling-virtual-screening-and-docking-approach
#7
S Haidar, R W Hartmann
17α-Hydroxylase/C17-20-lyase (P450 17, CYP 17) is an important enzyme in the androgen biosynthesis and inhibitors of this enzyme can be used for the treatment of prostate cancer. With the aim of developing new inhibitors for the target enzyme, we generated a structure-based pharmacophore model to further explain the binding requirements for human CYP17 inhibitors. Seven common features of steroidal CYP17 inhibitors were determined using MOE software. This pharmacophore model was then used to search the Cambridge Structural Database (CSD) with the aim of developing more potent and selective CYP17 inhibitors by identifying new hits...
September 1, 2017: Die Pharmazie
https://www.readbyqxmd.com/read/29440177/ponatinib-shows-potent-antitumor-activity-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-sccoht-through-multi-kinase-inhibition
#8
Jessica D Lang, William P D Hendricks, Krystal A Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Nanyun Tang, Winnie S Liang, Megan Washington, Salvatore J Facista, Victoria L Zismann, Emily M Cousins, Michael B Major, Yemin Wang, Anthony N Karnezis, Aleksandar Sekulic, Ralf Hass, Barbara C Vanderhyden, Praveen Nair, Bernard E Weissman, David G Huntsman, Jeffrey M Trent
PURPOSE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. EXPERIMENTAL DESIGN: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib...
February 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29438745/an-automated-epifluorescence-microscopy-imaging-assay-for-the-identification-of-phospho-akt-level-modulators-in-breast-cancer-cells
#9
Elke Kaemmerer, Dane Turner, Amelia A Peters, Sarah J Roberts-Thomson, Gregory R Monteith
AKT is an enzyme of the PI3K/pAKT pathway, regulating proliferation and cell survival. High basal levels of active, phosphorylated AKT (pAKT) are associated with tumor progression and therapeutic resistance in some breast cancer subtypes, including HER2 positive breast cancers. Various stimuli can increase pAKT levels and elevated basal pAKT levels are a feature of PTEN-deficient breast cancer cell lines. The aim of this study was to develop an assay able to identify modulators of pAKT levels using an automated epifluorescence microscope and high content analysis...
February 10, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29436980/virtual-screening-of-natural-inhibitors-targeting-ornithine-decarboxylase-with-pharmacophore-scaffolding-of-dfmo-and-validation-by-molecular-dynamics-simulation-studies
#10
Sivashanmugam Muthukumaran, K N Sulochana, V Umashankar
Ornithine Decarboxylase (ODC) is an enzyme that initiates polyamine synthesis in human. Polyamines play key roles in cell-cell adhesion, cell motility and Cell cycle regulation. Higher synthesis of polyamines also occurs in rapidly proliferating cancer cells are mediated by ODC. As per earlier studies, Di-Flouro Methyl Orninthine (DFMO) is a proven efficient inhibitor ODC targeting the catalytic activity, however, its usage is limited due to side effects. Targeting ODC is considered as a potential therapeutic modality in the treatment of cancer...
February 13, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29431189/molecular-analysis-of-palb2-associated-breast-cancers
#11
Jue Er Amanda Lee, Na Li, Simone M Rowley, Dane Cheasley, Magnus Zethoven, Simone McInerny, Kylie L Gorringe, Paul A James, Ian G Campbell
PALB2 is established as the most clinically important moderate to high penetrance breast cancer predisposition gene after BRCA1 and BRCA2. Mutations in classical familial cancer predisposition genes are presumed to be recessive at the cellular level and therefore a second inactivating somatic mutation is required in the tumour tissue. However, from the limited data that exists, PALB2 may be an example of a cancer predisposition gene that does not conform to Knudsen's "two hit" paradigm. We conducted genome-wide copy number analysis and targeted sequencing of PALB2 and other breast cancer driver genes in 15 invasive breast cancers from individuals carrying pathogenic germline mutations in PALB2...
February 12, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29423060/novel-cooperative-pathway-of-c-myc-and-furin-a-pro-protein-convertase-in-cell-proliferation-as-a-therapeutic-target-in-ovarian-cancers
#12
Junko Hasegawa-Minato, Masafumi Toyoshima, Masumi Ishibashi, Xuewei Zhang, Shogo Shigeta, Carla Grandori, Kazuyuki Kitatani, Nobuo Yaegashi
c-Myc is a master regulator of various oncogenic functions in many types of human cancers. However, direct c-Myc-targeted therapy has not been successful in the clinic. Here, we explored a novel therapeutic target, which shows synthetic lethality in c-Myc-driven ovarian cancers, and examined the molecular mechanism of the synthetic lethal interaction. By high throughput siRNA screening with a library of 6,550 genes, Furin, a pro-protein convertase, was identified as the top hit gene. Furin inhibition by siRNA or a Furin inhibitor significantly suppressed cell proliferation in high c-Myc-expressing ovarian cancer cells compared with low c-Myc-expressing cells...
January 9, 2018: Oncotarget
https://www.readbyqxmd.com/read/29422060/discovery-and-cellular-stress-pathway-analysis-of-1-4-naphthoquinone-derivatives-with-novel-highly-potent-broad-spectrum-anticancer-activity
#13
Sajal K Ghosh, Abhishek Ganta, Remco A Spanjaard
BACKGROUND: Chemotherapy and targeted therapies have made important strides in cancer treatment yet they often fail and new therapies are still needed. Here, we employed a phenotypic screen to identify and analyze the mechanism of action of novel small molecules that interfere with critical pathways involved in tumor cell growth, using chemoresistant A375 melanoma cells as a model. METHODS: Cell culture studies were performed in ATCC-recommended media. Compounds, and compound libraries were obtained from Boston University or purchased commercially...
February 8, 2018: Journal of Biomedical Science
https://www.readbyqxmd.com/read/29420531/differential-roles-of-the-drosophila-emt-inducing-transcription-factors-snail-and-serpent-in-driving-primary-tumour-growth
#14
Kyra Campbell, Gaëlle Lebreton, Xavier Franch-Marro, Jordi Casanova
Several transcription factors have been identified that activate an epithelial-to-mesenchymal transition (EMT), which endows cells with the capacity to break through basement membranes and migrate away from their site of origin. A key program in development, in recent years it has been shown to be a crucial driver of tumour invasion and metastasis. However, several of these EMT-inducing transcription factors are often expressed long before the initiation of the invasion-metastasis cascade as well as in non-invasive tumours...
February 8, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29420364/assessing-patient-reported-quality-of-life-outcomes-in-vulva-cancer-patients-a-systematic-literature-review
#15
Ligita Paskeviciute Froeding, Elfriede Greimel, Anne Lanceley, Anne Oberguggenberger, Claudia Schmalz, Vesna Bjelic Radisic, Andy Nordin, Razvan Galalaei, Karin Kuljanic, Ingvild Vistad, Tine Henrichsen Schnack, Pernille Tine Jensen
OBJECTIVES: Vulva cancer (VC) treatment carries a high risk of severe late effects that may have a negative impact on quality of life (QoL). Patient-reported outcome measures (PROMs) are increasingly used when evaluating disease- and treatment-specific effects. However, the adequacy of measures used to assess sequelae and QoL in VC remains unclear. The aims of the present study were to evaluate disease- and treatment-related effects as measured by PROMs in VC patients and to identify available VC-specific PROMs...
February 8, 2018: International Journal of Gynecological Cancer
https://www.readbyqxmd.com/read/29417867/bioinformatic-analyses-of-microrna-targeted-genes-and-microarray-identified-genes-correlated-with-barrett-s-esophagus
#16
Jing Lv, Jijun Liu, Lei Guo, Jun Zhang, Yan Cheng, Chu Chen, Heping Zhao, Jihan Wang
Barrett's esophagus (BE) is defined as a metaplasia condition in the distal esophagus, in which the native squamous epithelium lining is replaced by a columnar epithelium with or without intestinal metaplasia. It is commonly accepted that BE is a precancerous lesion for esophageal adenocarcinoma. The aim of this study was to investigate the aberrant microRNAs (miRNAs) and differentially expressed genes (DEGs) associated with BE based on online microarray datasets. One miRNA and five gene expression profiling datasets were retrieved from the Gene Expression Omnibus Database...
February 8, 2018: Cell Cycle
https://www.readbyqxmd.com/read/29411994/anticancer-metallodrugs-where-is-the-next-cisplatin
#17
Muhammad Hanif, Christian G Hartinger
Despite the severe side effects and the emergence of drug resistance, the use of DNA-targeting platinum drugs remains strong either alone or in a combination chemotherapy regimen. New strategies and formulations are being explored in the design of anticancer metal complexes that exhibit nonclassical modes of action, selectively hit precise biomolecular targets or are even able to induce immunogenic anticancer activity. These developments will ameliorate the systemic toxicity of metal-based drugs and widen the range of treatable cancers...
February 7, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29411820/structure-based-discovery-of-new-maternal-embryonic-leucine-zipper-kinase-inhibitors
#18
Shu Zhou, Guo-Bo Li, Lin Luo, Lei Zhong, Kai Chen, Hui Li, Xiao-Juan Jiang, Qi Fu, Xin Long, Jin-Ku Bao
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3...
February 7, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29407975/novel-vitexin-inspired-scaffold-against-leukemia
#19
Taotao Ling, Walter Lang, Xiang Feng, Sourav Das, Julie Maier, Cynthia Jeffries, Anang Shelat, Fatima Rivas
Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Up to a quarter of ALL patients relapse and face poor prognosis. To identify new compound leads, we conducted a phenotypic screen using terrestrial natural product (NP) fractions against immortalized ALL cellular models. We identified vitexin, a flavonoid, as a promising hit with biological activity (EC50 = 30 μM) in pre-B cell ALL models with no toxicity against normal human tissue (BJ cells) at the tested concentrations...
January 30, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29406586/erratum-epperla-n-maddocks-kj-salhab-m-et-al-c-myc-positive-relapsed-and-refractory-diffuse-large-b-cell-lymphoma-impact-of-additional-hits-and-outcomes-with-subsequent-therapy-cancer-2017-123-4411-4418
#20
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