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https://www.readbyqxmd.com/read/29688721/nano-encapsulation-of-novel-inhibitors-of-pnkp-for-selective-sensitization-to-ionizing-radiation-and-irinotecan-and-induction-of-synthetic-lethality
#1
Zahra Shire, Mohammad Reza Vakili, Timothy D R Morgan, Dennis G Hall, Afsaneh Lavasanifar, Michael Weinfeld
There is increasing interest in developing and applying DNA repair inhibitors in cancer treatment to augment the efficacy of radiation and conventional genotoxic chemotherapy. However, targeting the inhibitor is required to avoid reducing the repair capacity of normal tissue. The aim of this study was to develop nano-delivery systems for the encapsulation of novel imidopiperidine-based inhibitors of the DNA 3'-phosphatase activity of polynucleotide kinase/phosphatase (PNKP), a DNA repair enzyme that plays a critical role in rejoining DNA single- and double-strand breaks...
April 24, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29688013/fragment-based-drug-discovery-of-potent-protein-kinase-c-iota-inhibitors
#2
Jacek Kwiatkowski, Boping Liu, Doris Hui Ying Tee, Guoying Chen, Nur Huda Binte Ahmad, Yun Xuan Wong, Zhi Ying Poh, Shi Hua Ang, Eldwin Sum Wai Tan, Esther Hq Ong, Nurul Dinie Binte Rahad, Anders Poulsen, Vishal Pendharkar, Kanda Sangthongpitag, May Ann Lee, Sugunavathi D/O Sepramaniam, Soo Yei Ho, Joseph Cherian, Jeffrey Hill, Thomas H Keller, Alvin W Hung
Protein Kinase C iota is an atypical kinase implicated in the promotion of different cancer types. A fragment-based screen has identified several hits, from which an azaindole-based scaffold was chosen for optimization. Driven by structure-activity relationship and supported by molecular modelling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-iota.
April 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29685965/pyrazole-based-inhibitors-of-enhancer-of-zeste-homologue-2-induce-apoptosis-and-autophagy-in-cancer-cells
#3
Paolo Mellini, Biagina Marrocco, Diana Borovika, Lucia Polletta, Ilaria Carnevale, Serena Saladini, Giulia Stazi, Clemens Zwergel, Peteris Trapencieris, Elisabetta Ferretti, Marco Tafani, Sergio Valente, Antonello Mai
Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o ( N -((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methyl-1-phenyl-1 H -pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy...
June 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29683402/identification-and-evaluation-of-bioactive-natural-products-as-potential-inhibitors-of-human-microtubule-affinity-regulating-kinase-4-mark4
#4
Taj Mohammad, Faez Iqbal Khan, Kevin A Lobb, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Microtubule affinity-regulating kinase 4 (MARK4) has recently been identified as a potential drug target for several complex diseases including cancer, diabetes and neurodegenerative disorders. Inhibition of MARK4 activity is an appealing therapeutic option to treat such diseases. Here, we have performed structure-based virtual high-throughput screening of 100,000 naturally occurring compounds from ZINC database against MARK4 to find its potential inhibitors. The resulted hits were selected based on the binding affinities, docking scores and selectivity...
April 23, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29683269/multiple-machine-learning-based-chemoinformatics-models-for-identification-of-histone-acetyl-transferase-inhibitors
#5
Shagun Krishna, Sushil Kumar, Deependra Kumar Singh, Amar Deep Lakra, Dibyendu Banerjee, Mohammad Imran Siddiqi
The histone acetyl transferase (HAT) are involved in acetylation of histones that lead to transcription activation in numerous gene regulatory mechanisms. There are very few GCN5 HAT inhibitors reported despite of their role in cancer progression. In this study, we have utilized in-silico virtual screening approaches based on various machine learning algorithm to identify potent inhibitors of GCN5 HAT from commercially available Maybridge library. We have generated predictive chemoinformatics models based on k-Nearest neighbour, naïve Bayesian, Random Forest and Support Vector Machine...
April 23, 2018: Molecular Informatics
https://www.readbyqxmd.com/read/29682501/vdac1-as-pharmacological-target-in-cancer-and-neurodegeneration-focus-on-its-role-in-apoptosis
#6
REVIEW
Andrea Magrì, Simona Reina, Vito De Pinto
Cancer and neurodegeneration are different classes of diseases that share the involvement of mitochondria in their pathogenesis. Whereas the high glycolytic rate (the so-called Warburg metabolism) and the suppression of apoptosis are key elements for the establishment and maintenance of cancer cells, mitochondrial dysfunction and increased cell death mark neurodegeneration. As a main actor in the regulation of cell metabolism and apoptosis, VDAC may represent the common point between these two broad families of pathologies...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29679863/discovery-of-new-gyrase-%C3%AE-inhibitors-via-structure-based-modeling
#7
Afaf H Al-Nadaf, Sajeda A Salah, Mutasem O Taha
Gyrase B is an essential enzyme in the prokaryotes which became an attractive target for antibacterial agents. In our study, we implemented a wide range of docking configurations to dock 120 inhibitors into the in the ATP- binding pocket of Gyrase B enzyme (PDB code: 4GEE). LigandFit docking engines and six scoring functions were utilized in the study. Furthermore, the ligands were docked in their ionized and unionized forms into the hydrous and anhydrous binding pocket. We used docking-based Comparative Intermolecular Contacts Analysis (db-CICA) which is a novel methodology to validate and identify the optimal docking configurations...
March 19, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29676157/high-throughput-assay-for-collagen-secretion-suggests-an-unanticipated-role-for-hsp90-in-collagen-production
#8
Madeline Y Wong, Ngoc Duc Doan, Andrew S DiChiara, Louis J Papa, Jaime H Cheah, Christian K Soule, Nicki Watson, John D Hulleman, Matthew D Shoulders
Collagen overproduction is a feature of fibrosis and cancer, while insufficient deposition of functional collagen molecules and/or the secretion of malformed collagen are common in genetic disorders like osteogenesis imperfecta. Collagen secretion is an appealing therapeutic target in these and other diseases, as secretion directly connects intracellular biosynthesis to collagen deposition and biological function in the extracellular matrix. However, small molecule and biological methods to tune collagen secretion are severely lacking...
April 20, 2018: Biochemistry
https://www.readbyqxmd.com/read/29671617/oxazole-and-thiazole-analogs-of-sulindac-for-cancer-prevention
#9
Bini Mathew, Judith V Hobrath, Michele C Connelly, R Kiplin Guy, Robert C Reynolds
AIM: Experimental and epidemiological studies and clinical trials suggest that nonsteroidal anti-inflammatory drugs possess antitumor potential. Sulindac, a widely used nonsteroidal anti-inflammatory drug, can prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA) is an amide-linked sulindac sulfide analog that showed in vivo antitumor activity in a human colon tumor xenograft model. Results/methodology: A new analog series with heterocyclic rings such as oxazole or thiazole at the C-2 position of sulindac was prepared and screened against prostate, colon and breast cancer cell lines to probe the effect of these novel substitutions on the activity of sulindac analogs...
April 19, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29661748/virtual-reality-cue-refusal-video-game-for-alcohol-and-cigarette-recovery-support-summative-study
#10
Mary Metcalf, Karen Rossie, Katie Stokes, Christina Tallman, Bradley Tanner
BACKGROUND: New technologies such as virtual reality, augmented reality, and video games hold promise to support and enhance individuals in addiction treatment and recovery. Quitting or decreasing cigarette or alcohol use can lead to significant health improvements for individuals, decreasing heart disease risk and cancer risks (for both nicotine and alcohol use), among others. However, remaining in recovery from use is a significant challenge for most individuals. OBJECTIVE: We developed and assessed the Take Control game, a partially immersive Kinect for Windows platform game that allows users to counter substance cues through active movements (hitting, kicking, etc)...
April 16, 2018: JMIR Serious Games
https://www.readbyqxmd.com/read/29645362/structural-plasticity-of-the-tdrd3-tudor-domain-probed-by-a-fragment-screening-hit
#11
Jiuyang Liu, Shuya Zhang, Mingqing Liu, Yaqian Liu, Gilbert Nshogoza, Jia Gao, Rongsheng Ma, Yang Yang, Jihui Wu, Jiahai Zhang, Fudong Li, Ke Ruan
As a reader of di-methylated arginine on various proteins, such as histone, RNA polymerase II, PIWI and Fragile X mental retardation protein, the Tudor domain of Tudor domain-containing protein 3 (TDRD3) mediates transcriptional activation in nucleus and formation of stress granules in the cytoplasm. Despite the TDRD3 implication in cancer cell proliferation and invasion, warheads to block the di-methylated arginine recognition pocket of the TDRD3 Tudor domain have not yet been uncovered. Here we identified 14 small molecule hits against the TDRD3 Tudor domain through NMR fragment-based screening...
April 12, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29643052/the-effectiveness-of-health-care-information-technologies-evaluation-of-trust-security-beliefs-and-privacy-as-determinants-of-health-care-outcomes
#12
Victoria Kisekka, Justin Scott Giboney
BACKGROUND: The diffusion of health information technologies (HITs) within the health care sector continues to grow. However, there is no theory explaining how success of HITs influences patient care outcomes. With the increase in data breaches, HITs' success now hinges on the effectiveness of data protection solutions. Still, empirical research has only addressed privacy concerns, with little regard for other factors of information assurance. OBJECTIVE: The objective of this study was to study the effectiveness of HITs using the DeLone and McLean Information Systems Success Model (DMISSM)...
April 11, 2018: Journal of Medical Internet Research
https://www.readbyqxmd.com/read/29629667/anticancer-pyrrolizines-design-synthesis-caspase-3-activation-and-micronucleus-mn-induction
#13
Amany Belal
For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method...
April 9, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29625052/pathogenic-germline-variants-in-10-389-adult-cancers
#14
Kuan-Lin Huang, R Jay Mashl, Yige Wu, Deborah I Ritter, Jiayin Wang, Clara Oh, Marta Paczkowska, Sheila Reynolds, Matthew A Wyczalkowski, Ninad Oak, Adam D Scott, Michal Krassowski, Andrew D Cherniack, Kathleen E Houlahan, Reyka Jayasinghe, Liang-Bo Wang, Daniel Cui Zhou, Di Liu, Song Cao, Young Won Kim, Amanda Koire, Joshua F McMichael, Vishwanathan Hucthagowder, Tae-Beom Kim, Abigail Hahn, Chen Wang, Michael D McLellan, Fahd Al-Mulla, Kimberly J Johnson, Olivier Lichtarge, Paul C Boutros, Benjamin Raphael, Alexander J Lazar, Wei Zhang, Michael C Wendl, Ramaswamy Govindan, Sanjay Jain, David Wheeler, Shashikant Kulkarni, John F Dipersio, Jüri Reimand, Funda Meric-Bernstam, Ken Chen, Ilya Shmulevich, Sharon E Plon, Feng Chen, Li Ding
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events...
April 5, 2018: Cell
https://www.readbyqxmd.com/read/29622910/ethnomedicine-claim-directed-in-silico-prediction-of-anticancer-activity
#15
Biniyam Girma, Eshetu Mulisa, Shibru Tessema, Wote Amelo
Background: The merits of ethnomedicine-led approach to identify and prioritize anticancer medicinal plants have been challenged as cancer is more likely to be poorly understood in traditional medicine practices. Nonetheless, it is also believed that useful data can be generated by combining ethnobotanical findings with available scientific studies. Thus, this study combined an ethnobtanical study with ligand based in silico screening to identify relevant medical plants and predict their anticancer potential based on their phytoconstiutents reported in scientific literatures...
January 2018: Ethiopian Journal of Health Sciences
https://www.readbyqxmd.com/read/29617658/machine-learning-detects-pan-cancer-ras-pathway-activation-in-the-cancer-genome-atlas
#16
Gregory P Way, Francisco Sanchez-Vega, Konnor La, Joshua Armenia, Walid K Chatila, Augustin Luna, Chris Sander, Andrew D Cherniack, Marco Mina, Giovanni Ciriello, Nikolaus Schultz, Yolanda Sanchez, Casey S Greene
Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29615704/virtual-screening-docking-admet-and-system-pharmacology-studies-on-garcinia-caged-xanthone-derivatives-for-anticancer-activity
#17
Sarfaraz Alam, Feroz Khan
Caged xanthones are bioactive compounds mainly derived from the Garcinia genus. In this study, a structure-activity relationship (SAR) of caged xanthones and their derivatives for anticancer activity against different cancer cell lines such as A549, HepG2 and U251 were developed through quantitative (Q)-SAR modeling approach. The regression coefficient (r2 ), internal cross-validation regression coefficient (q2 ) and external cross-validation regression coefficient (pred_r2 ) of derived QSAR models were 0.87, 0...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29614516/identification-of-non-zinc-binding-inhibitors-of-mmp-2-through-virtual-screening-and-subsequent-rescoring
#18
Jamal Shamsara
MMP-2 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type IV collagen, the main structural component of basement membranes and gelatin. The main pathologic role of MMP-2 overexpression is to contribute to the development of cancer through the progression of metastasis and angiogenesis. A structure-based virtual screening was employed to find new inhibitors with possible selectivity for MMP-2. The inhibitory activities of 3 inhibitors (one was not a suitable drug-like hit) among 19 purchased compounds were approved by enzyme inhibition assay...
April 3, 2018: Drug Research
https://www.readbyqxmd.com/read/29603892/niclosamide-a-drug-with-many-re-purposes
#19
Hachemi Kadri, Olivia A Lambourne, Youcef Mehellou
Niclosamide is an anthelmintic drug that has mainly been used for over 50 years to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease, diabetes, viral and microbial infections as well as various cancers. Such diverse pharmacological activities are a result of niclosamide's ability to uncouple mitochondrial phosphorylation and modulate a selection of signaling pathways, such as Wnt/β-catenin, mTOR and JAK/STAT3, which are implicated many diseases...
March 30, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29594019/stopping-screening-when-and-how
#20
REVIEW
Jonas Hugosson
Screening for prostate cancer (PC) is still controversial despite randomized trials has found that PC mortality is decreased. The major concern is the high rate of over-diagnosis and subsequent harms that may follow in many men who never would have had any symptoms during life-time if not screened. The high rate of over-diagnosis is driven by the large reservoir of small non-significant cancers that increases with age and found in more than half of men over 70 years, the low specificity of prostate specific antigen (PSA) but also by current "blind" biopsy technique that risk accidentally to hit these small non-significant cancers...
February 2018: Translational Andrology and Urology
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