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https://www.readbyqxmd.com/read/28207202/the-polar-warhead-of-a-trim24-bromodomain-inhibitor-rearranges-a-water-mediated-interaction-network
#1
Jiuyang Liu, Fudong Li, Hongyu Bao, Yiyang Jiang, Shuya Zhang, Rongsheng Ma, Jia Gao, Jihui Wu, Ke Ruan
Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors...
February 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28199108/application-of-off-rate-screening-in-the-identification-of-novel-pan-isoform-inhibitors-of-pyruvate-dehydrogenase-kinase
#2
Paul A Brough, Lisa Baker, Simon Bedford, Kirsten Brown, Seema Chavda, Victoria Chell, Jalanie D'Alessandro, Nicholas G M Davies, Ben Davis, Loic Le Strat, Alba T Macias, Daniel Maddox, Patrick C Mahon, Andrew J Massey, Natalia Matassova, Sean McKenna, Jonathan D Moore, James B Murray, Christopher J Northfield, Charles Parry, Rachel Parsons, Stephen D Roughley, Terry Shaw, Heather Simmonite, Stephen Stokes, Allan Surgenor, Emma Stefaniak, Alan Robertson, Yikang Wang, Paul Webb, Neil Whitehead, Mike Wood
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro...
February 15, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28198289/help-patients-cope-with-the-financial-toll-of-cancer
#3
Lynne Pearce
Macmillan Cancer Support estimates that cancer costs an average of £570 a month for more than eight in ten patients, with working parents of young children hit hardest of all.
February 15, 2017: Nursing Standard
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#4
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28191946/in-search-of-novel-cdk8-inhibitors-by-virtual-screening
#5
Malika Kumarasiri, Theodosia Teo, Mingfeng Yu, Stephen Philip, Sunita K C Basnet, Hugo Albrecht, Matthew J Sykes, Peng Wang, Shudong Wang
Aberrant activity of cyclin-dependent kinase (CDK) 8 is implicated in various cancers. While CDK8-targeting anticancer drugs are highly sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein a large library of drug-like molecules was computationally screened using two complementary cascades to identify potential CDK8 inhibitors. Thirty-three hits were identified to inhibit CDK8 and seven of them were active against colorectal cancer cell lines. Finally, the primary target was confirmed using three promising hits...
February 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28168682/a-magnetic-resonance-image-guided-breast-needle-intervention-robot-system-overview-and-design-considerations
#6
Samuel Byeongjun Park, Jung-Gun Kim, Ki-Woong Lim, Chae-Hyun Yoon, Dong-Jun Kim, Han-Sung Kang, Yung-Ho Jo
PURPOSE: We developed an image-guided intervention robot system that can be operated in a magnetic resonance (MR) imaging gantry. The system incorporates a bendable needle intervention robot for breast cancer patients that overcomes the space limitations of the MR gantry. METHODS: Most breast coil designs for breast MR imaging have side openings to allow manual localization. However, for many intervention procedures, the patient must be removed from the gantry. A robotic manipulation system with integrated image guidance software was developed...
February 6, 2017: International Journal of Computer Assisted Radiology and Surgery
https://www.readbyqxmd.com/read/28168164/vdac-tubulin-an-anti-warburg-pro-oxidant-switch
#7
REVIEW
Eduardo N Maldonado
Aerobic enhanced glycolysis characterizes the Warburg phenotype. In cancer cells, suppression of mitochondrial metabolism contributes to maintain a low ATP/ADP ratio that favors glycolysis. We propose that the voltage-dependent anion channel (VDAC) located in the mitochondrial outer membrane is a metabolic link between glycolysis and oxidative phosphorylation in the Warburg phenotype. Most metabolites including respiratory substrates, ADP, and Pi enter mitochondria only through VDAC. Oxidation of respiratory substrates in the Krebs cycle generates NADH that enters the electron transport chain (ETC) to generate a proton motive force utilized to generate ATP and to maintain mitochondrial membrane potential (ΔΨ)...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28166232/repositioning-approved-drugs-for-the-treatment-of-problematic-cancers-using-a-screening-approach
#8
Hristo P Varbanov, Fabien Kuttler, Damiano Banfi, Gerardo Turcatti, Paul J Dyson
Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types...
2017: PloS One
https://www.readbyqxmd.com/read/28157066/multiparametric-mri-in-detection-and-staging-of-prostate-cancer
#9
Lars Boesen
BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related mortality and the most frequently diagnosed male malignant disease among men in the Nordic countries. The manifestation of PCa ranges from indolent to highly aggressive disease and due to this high variation in PCa progression, the diagnosis and subsequent treatment planning can be challenging. The current diagnostic approach with PSA testing and digital rectal examination followed by transrectal ultrasound biopsies (TRUS-bx) lack in both sensitivity and specificity in PCa detection and offers limited information about the aggressiveness and stage of the cancer...
February 2017: Danish Medical Journal
https://www.readbyqxmd.com/read/28155652/evaluating-the-effect-of-database-inflation-in-proteogenomic-search-on-sensitive-and-reliable-peptide-identification
#10
Honglan Li, Yoon Sung Joh, Hyunwoo Kim, Eunok Paek, Sang-Won Lee, Kyu-Baek Hwang
BACKGROUND: Proteogenomics is a promising approach for various tasks ranging from gene annotation to cancer research. Databases for proteogenomic searches are often constructed by adding peptide sequences inferred from genomic or transcriptomic evidence to reference protein sequences. Such inflation of databases has potential of identifying novel peptides. However, it also raises concerns on sensitive and reliable peptide identification. Spurious peptides included in target databases may result in underestimated false discovery rate (FDR)...
December 22, 2016: BMC Genomics
https://www.readbyqxmd.com/read/28153734/high-throughput-screening-for-survivin-and-borealin-interaction-inhibitors-in-hepatocellular-carcinoma
#11
Liyun Yue, Lu Li, Dan Li, Zhuo Yang, Shuai Han, Ming Chen, Shujue Lan, Xiaojun Xu, Lijian Hui
Survivin, a key member of the chromatin passenger complex (CPC), is often highly expressed in human cancers, making it a promising target for cancer treatment. Out of the numerous reported Survivin inhibitors, YM155 is only one entering clinical trial, but was recently failed in the Phase II trial. It is important to develop Survivin inhibitors with new strategies. We recently reported that both Survivin and its binding protein Borealin in the CPC complex are essential for the development of hepatocellular carcinoma, suggesting that disrupting the interaction between Survivin and Borealin would be a promising strategy...
January 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28150878/pathway-analysis-of-published-genome-wide-association-studies-of-lung-cancer-a-potential-role-for-the-cyp4f3-locus
#12
Jieyun Yin, Hongliang Liu, Zhensheng Liu, Kouros Owzar, Younghun Han, Li Su, Yongyue Wei, Rayjean J Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeboeller, Albert Rosenberger, Richard S Houlston, Neil Caporaso, Maria Teresa Landi, Joachim Heinrich, Angela Risch, David C Christiani, Christopher I Amos, Qingyi Wei
The Fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, we explored that by conducting pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12,160 cases with lung cancer and 16,838 cancer-free controls. A total of 30,722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified...
February 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28145708/identification-of-triazolothiadiazoles-as-potent-inhibitors-of-the-dctp-pyrophosphatase-1
#13
Sabin Llona-Minguez, Anders Höglund, Elisee Wiita, Ingrid Almlöf, André Mateus, José Manuel Calderón-Montaño, Cindy Cazares-Körner, Evert J Homan, Olga Loseva, Pawel Baranczewski, Ann-Sofie Jemth, Maria Häggblad, Ulf Martens, Bo Lundgren, Per Artursson, Thomas Lundbäck, Annika Jenmalm-Jensen, Ulrika Warpman Berglund, Martin Scobie, Thomas Helleday
The dCTP pyrophosphatase 1 (dCTPase) is involved in the regulation of the cellular dNTP pool and has been linked to cancer progression. Here we report on the discovery of a series of 3,6-disubstituted triazolothiadiazoles as potent dCTPase inhibitors. Compound 16 and 18 display good correlation between enzymatic inhibition and target engagement, together with efficacy in a cellular synergy model, deeming them as a promising starting point for hit-to-lead development.
February 1, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28138797/exploiting-micrornas-as-cancer-therapeutics
#14
Tamsin Robb, Glen Reid, Cherie Blenkiron
miRNAs are a well-studied class of non-coding RNAs, predominantly functioning to down-regulate gene expression from messenger RNA (mRNA) in a targeted manner by binding to complementary sequence on the target mRNA. Many miRNAs have been linked to the development of hallmarks of cancer. miRNAs represent valuable therapeutic targets to exploit in the search for novel cancer treatments, due to their ubiquitous expression and their ability to tightly regulate the gene expression of a whole host of genes and pathways in a single hit...
January 30, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/28129980/discovery-of-furan-carboxylate-derivatives-as-novel-inhibitors-of-atp-citrate-lyase-via-virtual-high-throughput-screening
#15
Finith E Jernigan, Jun-Ichi Hanai, Vikas P Sukhatme, Lijun Sun
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms...
January 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28122174/synthesis-qsar-studies-and-metabolic-stability-of-novel-2-alkylthio-4-chloro-n-5-oxo-4-5-dihydro-1-2-4-triazin-3-yl-benzenesulfonamide-derivatives-as-potential-anticancer-and-apoptosis-inducing-agents
#16
Beata Żołnowska, Jarosław Sławiński, Aneta Pogorzelska, Krzysztof Szafrański, Anna Kawiak, Grzegorz Stasiłojć, Mariusz Belka, Joanna Zielińska, Tomasz Bączek
A series of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives 12-46 have been synthesized by the reaction of aminoguanidines with an appropriate alpha-oxo-acids hydrates in glacial acetic acid. All the synthesized compounds were evaluated for their anticancer activity against HeLa, HCT-116 and MCF-7 human tumor cell lines. Two compounds 33 and 34 displayed outstanding cytotoxic effect selectively toward HeLa cancer cells (IC50 = 19 μM) and did not exhibit toxicity to the non-cancerous HaCaT cells...
January 25, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28116879/physical-activity-in-the-prevention-and-management-of-bladder-cancer
#17
Roy J Shephard
INTRODUCTION: The aim was to examine the role of physical activity in reducing the risk of bladder cancer, and in managing established disease. EVIDENCE ACQUISITION: A systematic search of Ovid/Medline from 1996 to June 2016 coupled the term urinary bladder neoplasms (25,061 hits) with markers of physical activity (exercise, physical activity, physical education/training, athletes, and physical fitness, a total of 246,683 unique entries). Of 42 titles identified, 18 relevant abstracts were supplemented by reviewing reference lists and personal files to yield 21 articles on prevention of bladder cancer, and 8 on physical activity in disease management...
January 23, 2017: Journal of Sports Medicine and Physical Fitness
https://www.readbyqxmd.com/read/28114909/low-glycemic-index-diet-exercise-and-vitamin-d-to-reduce-breast-cancer-recurrence-dedica-design-of-a-clinical-trial
#18
Livia S A Augustin, Massimo Libra, Anna Crispo, Maria Grimaldi, Michele De Laurentiis, Massimo Rinaldo, Massimiliano D'Aiuto, Francesca Catalano, Giuseppe Banna, Francesco Ferrau', Rosalba Rossello, Diego Serraino, Ettore Bidoli, Samuele Massarut, Guglielmo Thomas, Davide Gatti, Ernesta Cavalcanti, Monica Pinto, Gabriele Riccardi, Edward Vidgen, Cyril W C Kendall, David J A Jenkins, Gennaro Ciliberto, Maurizio Montella
BACKGROUND: Mechanisms influencing breast cancer (BC) development and recurrence include hyperglycemia, hyperinsulinemia, high insulin-like growth factor-1, high circulating estrogen, inflammation and impaired cellular differentiation/apoptosis. A lifestyle program that targets all the above mechanisms may be warranted. Low glycemic index (GI) foods produce lower post-prandial glucose and insulin responses and have been associated with lower BC risk. Moderate physical activity post-diagnosis reduces BC recurrence and mortality, partly explained by reduced insulin and estrogen levels...
January 23, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28114112/secondary-radiation-measurements-for-particle-therapy-applications-prompt-photons-produced-by-4-he-12-c-and-16-o-ion-beams-in-a-pmma-target
#19
I Mattei, F Bini, F Collamati, E De Lucia, P M Frallicciardi, E Iarocci, C Mancini-Terracciano, M Marafini, S Muraro, R Paramatti, V Patera, L Piersanti, D Pinci, A Rucinski, A Russomando, A Sarti, A Sciubba, E Solfaroli Camillocci, M Toppi, G Traini, C Voena, G Battistoni
Charged particle beams are used in particle therapy (PT) to treat oncological patients due to their selective dose deposition in tissues with respect to the photons and electrons used in conventional radiotherapy. Heavy (Z  >  1) PT beams can additionally be exploited for their high biological effectiveness in killing cancer cells. Nowadays, protons and carbon ions are used in PT clinical routines. Recently, interest in the potential application of helium and oxygen beams has been growing. With respect to protons, such beams are characterized by their reduced multiple scattering inside the body, increased linear energy transfer, relative biological effectiveness and oxygen enhancement ratio...
February 21, 2017: Physics in Medicine and Biology
https://www.readbyqxmd.com/read/28112925/highly-potent-non-carboxylic-acid-autotaxin-inhibitors-reduce-melanoma-metastasis-and-chemotherapeutic-resistance-of-breast-cancer-stem-cells
#20
Souvik Banerjee, Derek D Norman, Sue Chin Lee, Abby L Parrill, Truc Chi T Pham, Daniel L Baker, Gabor J Tigyi, Duane D Miller
Autotaxin (ATX, aka. ENPP2) is the main source of the lipid mediator lysophosphatidic acid (LPA) in biological fluids. This study reports on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues provide a comprehensive structure-activity relationship of the benzene-sulfonamide scaffold that yielded a series of highly potent ATX inhibitors. The three most potent analogues (3a, IC50 ∼ 32 nM; 3b, IC50 ∼ 9 nM; and 14, IC50 ∼ 35 nM) inhibit ATX-dependent invasion of A2058 human melanoma cells in vitro...
February 10, 2017: Journal of Medicinal Chemistry
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