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SLAS Discovery

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https://www.readbyqxmd.com/read/30418800/inexpensive-high-throughput-screening-of-kinase-inhibitors-using-one-step-enzyme-coupled-fluorescence-assay-for-adp-detection
#1
Riyo Maruki Imamura, Kazuo Kumagai, Hirofumi Nakano, Takayoshi Okabe, Tetsuo Nagano, Hirotatsu Kojima
Protein kinases are attractive targets for both biological research and drug development. Several assay kits, especially for the detection of adenosine diphosphate (ADP), which is universally produced by kinases, are commercially available for high-throughput screening (HTS) of kinase inhibitors, but their cost is quite high for large-scale screening. Here, we report a new enzyme-coupled fluorescence assay for ADP detection, which uses just 10 inexpensive, commercially available components. The assay protocol is very simple, requiring only the mixing of test solutions with ADP detection solution and reading the fluorescence intensity of resorufin produced by coupling reaction...
November 12, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30383474/a-new-model-of-sensorial-neuron-like-cells-for-hts-of-novel-analgesics-for-neuropathic-pain
#2
Antón L Martínez, José Brea, Xavier Monroy, Manuel Merlos, Javier Burgueño, María Isabel Loza
In this study we developed a new translational phenotypic in vitro model for high-throughput screening (HTS) of novel analgesics for treating neuropathic pain, in order to address the poor translation of traditional recombinant models. The immortalized dorsal root ganglia (DRG) neuron-like F11 cell line was selected based on its phenotype after differentiation. The acquisition of neuronal characteristics was evaluated by measuring the expression of TrkA as a DRG neuron marker ( p < 0.01) as well as by measuring the global neurite length ( p < 0...
November 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30383469/development-of-a-high-throughput-cul3-keap1-time-resolved-fluorescence-resonance-energy-transfer-tr-fret-assay-for-identifying-nrf2-activators
#3
Derek D Poore, Glenn Hofmann, Lawrence A Wolfe, Hongwei Qi, Ming Jiang, Michael Fischer, Zining Wu, Thomas D Sweitzer, Subhas Chakravorty, Brian Donovan, Hu Li
Nrf2, a master regulator of the phase II gene response to stress, is kept at low concentrations in the cell through binding to Keap1, an adaptor protein for the Cul3 ubiquitin ligase complex. To identify Nrf2 activators, two separate time-resolved fluorescence resonance energy transfer (TR-FRET) assays were developed to monitor the binding of Nrf2-Keap1 and Cul3-Keap1, respectively. The triterpenoid, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole (CDDO-Im) and its analogs, exhibited approximately 100-fold better potency in the Cul3-Keap1 assay than in the Nrf2-Keap1 assay, and this difference was more profound at 37 °C than at room temperature in the Nrf2-Keap1 assay, but this phenomenon was not observed in the Cul3-Keap1 assay...
November 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30383465/development-of-a-selection-method-for-discovering-irreversible-covalent-binders-from-a-dna-encoded-library
#4
Zhengrong Zhu, LaShadric C Grady, Yun Ding, Kenneth E Lind, Christopher P Davie, Christopher B Phelps, Ghotas Evindar
DNA-encoded libraries (DELs) have been broadly applied to identify chemical probes for target validation and lead discovery. To date, the main application of the DEL platform has been the identification of reversible ligands using multiple rounds of affinity selection. Irreversible (covalent) inhibition offers a unique mechanism of action for drug discovery research. In this study, we report a developing method of identifying irreversible (covalent) ligands from DELs. The new method was validated by using 3C protease (3CP) and on-DNA irreversible tool compounds (rupintrivir derivatives) spiked into a library at the same concentration as individual members of that library...
November 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30359161/discovery-of-a-selective-inhibitor-for-the-yeats-domains-of-enl-af9
#5
Thomas Christott, James Bennett, Carmen Coxon, Octovia Monteiro, Charline Giroud, Viktor Beke, Suet Ling Felce, Vicki Gamble, Carina Gileadi, Gennady Poda, Rima Al-Awar, Gillian Farnie, Oleg Fedorov
Eleven-nineteen leukemia (ENL) contains an epigenetic reader domain (YEATS domain) that recognizes lysine acylation on histone 3 and facilitates transcription initiation and elongation through its interactions with the super elongation complex (SEC) and the histone methyl transferase DOT1L. Although it has been known for its role as a fusion protein in mixed lineage leukemia (MLL), overexpression of native ENL, and thus dysregulation of downstream genes in acute myeloid leukemia (AML), has recently been implicated as a driver of disease that is reliant on the epigenetic reader activity of the YEATS domain...
October 25, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30304643/development-of-a-bacterial-macroarray-for-the-rapid-screening-of-targeted-antibody-secreted-hybridomas
#6
Jie Li, XuZhao Zhai, Chengchao Ding, Yali Liu, Qingli Dong, Dongpo Xu, Xiang Wang, Jingxuan Qiu, Qi Zhang, Jing Pan, Qing Liu
Hybridoma screening is a key step for the successful generation of high-affinity analyte-specific monoclonal antibodies (MAbs). This work presents an innovative screening method, known as a bacterial macroarray, generated by contact printing of hybridoma cell supernatant samples on a nitrocellulose (NC) membrane initially coated with fluorescein isothiocyanate (FITC)-labeled bacteria. Given that bacterial fixation will be influenced by complex bacterial surface structures, we selected both gram-positive bacteria ( Staphylococcus aureus and Listeria monocytogenes) and gram-negative bacteria ( Escherichia coli O157:H7 and Cronobacter sakazakii) to optimize the fixation conditions for binding to the NC membrane, such as the aperture of the NC membrane, the concentration of bacteria, the dosage of glycerin in the spotting buffer, and the fixation time and temperature...
October 10, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30290128/high-throughput-dna-plasmid-transfection-using-acoustic-droplet-ejection-technology
#7
Béatrice Colin, Benoit Deprez, Cyril Couturier
The Labcyte Echo acoustic liquid handler allows accurate droplet ejection at high speed from a source well plate to a destination plate. It has already been used in various miniaturized biological assays, such as quantitative PCR (q-PCR), quantitative real-time PCR (q-RT-PCR), protein crystallization, drug screening, cell dispensing, and siRNA transfection. However, no plasmid DNA transfection assay has been published so far using this dispensing technology. In this study, we evaluated the ability of the Echo 550 device to perform plasmid DNA transfection in 384-well plates...
October 5, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30290126/design-of-the-lifearc-index-set-and-retrospective-review-of-its-performance-a-collection-for-sharing
#8
Kristian Birchall, Andy Merritt, Afrah Sattikar, Catherine Kettleborough, Barbara Saxty
Building, curating, and maintaining a compound collection is an expensive operation, beyond the scope of most academic organizations. Here we describe the selection criteria used to compile the LifeArc diversity set from commercial suppliers and the process we undertook to generate our representative LifeArc index set. The aim was to avoid a "junk in, junk out" screen collection to increase chemical tractability going forward, while maximizing diversity. Using historical LifeArc screening data, we demonstrate that the index set was predictive of ligandability and that progressable hits could be identified by mining associated clusters within our larger diversity set...
October 5, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30204534/development-of-high-throughput-screening-assays-for-inhibitors-of-ets-transcription-factors
#9
Simon L Currie, Steven L Warner, Hariprasad Vankayalapati, Xiaohui Liu, Sunil Sharma, David J Bearss, Barbara J Graves
ETS transcription factors from the ERG and ETV1/4/5 subfamilies are overexpressed in the majority of prostate cancer patients and contribute to disease progression. Here, we have developed two in vitro assays for the interaction of ETS transcription factors with DNA that are amenable to high-throughput screening. Using ETS1 as a model, we applied these assays to screen 110 compounds derived from a high-throughput virtual screen. We found that the use of lower-affinity DNA binding sequences, similar to those that ERG and ETV1 bind to in prostate cells, allowed for higher inhibition from many of these test compounds...
September 11, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30204533/identification-of-g-quadruplex-binding-inhibitors-of-myc-expression-through-affinity-selection-mass-spectrometry
#10
Deborah A Flusberg, Noreen F Rizvi, Victoria Kutilek, Christine Andrews, Peter Saradjian, Chad Chamberlin, Patrick Curran, Brooke Swalm, Sam Kattar, Graham F Smith, Peter Dandliker, Elliott B Nickbarg, Jennifer O'Neil
The Myc oncogene is overexpressed in many cancers, yet targeting it for cancer therapy has remained elusive. One strategy for inhibition of Myc expression is through stabilization of the G-quadruplex (G4), a G-rich DNA secondary structure found within the Myc promoter; stabilization of G4s has been shown to halt transcription of downstream gene products. Here we used the Automated Ligand Identification System (ALIS), an affinity selection-mass spectrometry method, to identify compounds that bind to the Myc G4 out of a pool of compounds that had previously been shown to inhibit Myc expression in a reporter screen...
September 11, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30196745/screening-strategies-and-methods-for-better-off-target-liability-prediction-and-identification-of-small-molecule-pharmaceuticals
#11
Terry R Van Vleet, Michael J Liguori, James J Lynch, Mohan Rao, Scott Warder
Pharmaceutical discovery and development is a long and expensive process that, unfortunately, still results in a low success rate, with drug safety continuing to be a major impedance. Improved safety screening strategies and methods are needed to more effectively fill this critical gap. Recent advances in informatics are now making it possible to manage bigger data sets and integrate multiple sources of screening data in a manner that can potentially improve the selection of higher-quality drug candidates. Integrated screening paradigms have become the norm in Pharma, both in discovery screening and in the identification of off-target toxicity mechanisms during later-stage development...
September 10, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30184441/identification-of-primary-natural-killer-cell-modulators-by-chemical-library-screening-with-a-luciferase-based-functional-assay
#12
Simon Hayek, Nassima Bekaddour, Laurie Besson, Rodolphe Alves de Sousa, Nicolas Pietrancosta, Sébastien Viel, Nikaia Smith, Yves Jacob, Sébastien Nisole, Rupasri Mandal, David S Wishart, Thierry Walzer, Jean-Philippe Herbeuval, Pierre-Olivier Vidalain
Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings...
September 5, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30142014/identification-of-antimalarial-inhibitors-using-late-stage-gametocytes-in-a-phenotypic-live-dead-assay
#13
Timothy P Spicer, Donald L Gardiner, Frank J Schoenen, Sudeshna Roy, Patrick R Griffin, Peter Chase, Louis Scampavia, Peter Hodder, Katharine R Trenholme
Malaria remains a major cause of morbidity and mortality worldwide with ~3.3 billion people at risk of contracting malaria and an estimated 450,000 deaths each year. While tools to reduce the infection prevalence to low levels are currently under development, additional efforts will be required to interrupt transmission. Transmission between human host and vector by the malaria parasite involves gametogenesis in the host and uptake of gametocytes by the mosquito vector. This stage is a bottleneck for reproduction of the parasite, making it a target for small-molecule drug discovery...
August 24, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30011241/homogeneous-btk-occupancy-assay-for-pharmacodynamic-assessment-of-tirabrutinib-gs-4059-ono-4059-target-engagement
#14
Helen Yu, Hoa Truong, Scott A Mitchell, Albert Liclican, John J Gosink, Wanying Li, Julie Lin, Joy Y Feng, Juliane M Jürgensmeier, Andrew Billin, Ren Xu, Scott Patterson, Nikos Pagratis
Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation...
October 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29842835/use-of-protein-kinase-focused-compound-libraries-for-the-discovery-of-new-inositol-phosphate-kinase-inhibitors
#15
Ana C Puhl-Rubio, Michael A Stashko, Huanchen Wang, P Brian Hardy, Vikas Tyagi, Bing Li, Xiaodong Wang, Dmitri Kireev, Henning J Jessen, Stephen V Frye, Stephen B Shears, Kenneth H Pearce
Inositol hexakisphosphate kinases (IP6Ks) regulate a myriad of cellular processes, not only through their catalytic activity (which synthesizes InsP7 , a multifunctional inositol pyrophosphate signaling molecule) but also through protein-protein interactions. To further study the enzymatic function and distinguish between these different mechanisms, specific inhibitors that target IP6K catalytic activity are required. Only one IP6K inhibitor is commonly used: N2-( m-(trifluoromethyl)benzyl) N6-( p-nitrobenzyl)purine (TNP)...
October 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29862873/clinical-trials-in-a-dish-a-perspective-on-the-coming-revolution-in-drug-development
#16
Bernard Fermini, Shawn T Coyne, Kevin P Coyne
The pharmaceutical industry is facing unprecedented challenges as the cost of developing new drugs has reached unsustainable levels, fueled in large parts by a high attrition rate in clinical development. Strategies to bridge studies between preclinical testing and clinical trials are needed to reduce the knowledge gap and allow earlier decisions to be made on the continuation or discontinuation of further development of drugs. The discovery and development of human induced pluripotent stem cells (hiPSCs) have opened up new avenues that support the concept of screening for cell-based safety and toxicity at the level of a population...
September 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29750582/a-cytotoxic-three-dimensional-spheroid-high-throughput-assay-using-patient-derived-glioma-stem-cells
#17
Victor Quereda, Shurong Hou, Franck Madoux, Louis Scampavia, Timothy P Spicer, Derek Duckett
Glioblastoma (GBM) is the most aggressive primary brain cancer with an average survival time after diagnosis of only 12-14 months, with few (<5%) long-term survivors. A growing body of work suggests that GBMs contain a small population of glioma stem cells (GSCs) that are thought to be major contributors to treatment resistance and disease relapse. Identifying compounds that modulate GSC proliferation would provide highly valuable molecular probes of GSC-directed signaling. However, targeting GSCs pharmacologically has been challenging...
September 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29742358/application-of-integrated-drug-screening-kinome-analysis-to-identify-inhibitors-of-gemcitabine-resistant-pancreatic-cancer-cell-growth
#18
Linas J Krulikas, Ian M McDonald, Benjamin Lee, Denis O Okumu, Michael P East, Thomas S K Gilbert, Laura E Herring, Brian T Golitz, Carrow I Wells, Allison D Axtman, William J Zuercher, Timothy M Willson, Dmitri Kireev, Jen Jen Yeh, Gary L Johnson, Antonio T Baines, Lee M Graves
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (MiaS ) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (MiaR ). In an effort to discover kinase inhibitors that inhibited MiaR growth, MiaR cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of MiaR cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor...
September 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29630847/screening-for-inhibitors-of-acetaldehyde-dehydrogenase-adhe-from-enterohemorrhagic-escherichia-coli-ehec
#19
Caroline E Zetterström, Pia Uusitalo, Weixing Qian, Shannon Hinch, Rémi Caraballo, Christin Grundström, Mikael Elofsson
Acetaldehyde dehydrogenase (AdhE) is a bifunctional acetaldehyde-coenzyme A (CoA) dehydrogenase and alcohol dehydrogenase involved in anaerobic metabolism in gram-negative bacteria. This enzyme was recently found to be a key regulator of the type three secretion (T3S) system in Escherichia coli. AdhE inhibitors can be used as tools to study bacterial virulence and a starting point for discovery of novel antibacterial agents. We developed a robust enzymatic assay, based on the acetaldehyde-CoA dehydrogenase activity of AdhE using both absorption and fluorescence detection models (Z' > 0...
September 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29543559/spontaneous-glioblastoma-spheroid-infiltration-of-early-stage-cerebral-organoids-models-brain-tumor-invasion
#20
Bárbara da Silva, Ryan K Mathew, Euan S Polson, Jennifer Williams, Heiko Wurdak
Organoid methodology provides a platform for the ex vivo investigation of the cellular and molecular mechanisms underlying brain development and disease. The high-grade brain tumor glioblastoma multiforme (GBM) is considered a cancer of unmet clinical need, in part due to GBM cell infiltration into healthy brain parenchyma, making complete surgical resection improbable. Modeling the process of GBM invasion in real time is challenging as it requires both tumor and neural tissue compartments. Here, we demonstrate that human GBM spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs)...
September 2018: SLAS Discovery
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