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SLAS Discovery

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https://www.readbyqxmd.com/read/30204534/development-of-high-throughput-screening-assays-for-inhibitors-of-ets-transcription-factors
#1
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
#2
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
#3
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
#4
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
#5
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/30102873/morphology-based-analysis-of-myoblasts-for-prediction-of-myotube-formation
#6
Kiyoshi Ishikawa, Kei Yoshida, Kei Kanie, Kenji Omori, Ryuji Kato
The development of new drugs depends on the efficiency of drug screening. Phenotype-based screening has attracted interest due to its considerable potency for the discovery of first-in-class drugs. In general, fluorescently labeled imagery is the leading technique for phenotype-based screening; however, there are growing requirements to understand total culture profiles, which are unclear after end-point assays. In this study, we demonstrate that morphology-based cellular evaluation of unlabeled cells is an efficient approach to evaluate myotube formation assays...
August 13, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30085848/development-of-a-screening-platform-to-identify-small-molecules-that-modify-elp1-pre-mrna-splicing-in-familial-dysautonomia
#7
Monica Salani, Fabio Urbina, Anthony Brenner, Elisabetta Morini, Ranjit Shetty, C Scott Gallagher, Emily A Law, Sara Sunshine, Dylan J Finneran, Graham Johnson, Lisa Minor, Susan A Slaugenhaupt
Familial dysautonomia (FD) is an autonomic and sensory neuropathy caused by a mutation in the splice donor site of intron 20 of the ELP1 gene. Variable skipping of exon 20 leads to a tissue-specific reduction in the level of ELP1 protein. We have shown that the plant cytokinin kinetin is able to increase cellular ELP1 protein levels in vivo and in vitro through correction of ELP1 splicing. Studies in FD patients determined that kinetin is not a practical therapy due to low potency and rapid elimination. To identify molecules with improved potency and efficacy, we developed a cell-based luciferase splicing assay by inserting renilla (Rluc) and firefly (Fluc) luciferase reporters into our previously well-characterized ELP1 minigene construct...
August 7, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30074852/image-based-detection-of-patient-specific-drug-induced-cell-cycle-effects-in-glioblastoma
#8
Damian J Matuszewski, Carolina Wählby, Cecilia Krona, Sven Nelander, Ida-Maria Sintorn
Image-based analysis is an increasingly important tool to characterize the effect of drugs in large-scale chemical screens. Herein, we present image and data analysis methods to investigate population cell-cycle dynamics in patient-derived brain tumor cells. Images of glioblastoma cells grown in multiwell plates were used to extract per-cell descriptors, including nuclear DNA content. We reduced the DNA content data from per-cell descriptors to per-well frequency distributions, which were used to identify compounds affecting cell-cycle phase distribution...
August 3, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30071751/high-throughput-screening-for-linear-ubiquitin-chain-assembly-complex-lubac-selective-inhibitors-using-homogenous-time-resolved-fluorescence-htrf-based-assay-system
#9
Ken Katsuya, Yuji Hori, Daisuke Oikawa, Tomohisa Yamamoto, Kayo Umetani, Toshiki Urashima, Tomomi Kinoshita, Kumiko Ayukawa, Fuminori Tokunaga, Masahiro Tamaru
The nuclear factor κB (NF-κB) pathway is critical for regulating immune and inflammatory responses, and uncontrolled NF-κB activation is closely associated with various inflammatory diseases and malignant tumors. The Met1-linked linear ubiquitin chain, which is generated by linear ubiquitin chain assembly complex (LUBAC), is important for regulating NF-κB activation. This process occurs through the linear ubiquitination of NF-κB essential modulator, a regulatory subunit of the canonical inhibitor of the NF-κB kinase complex...
August 2, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30063871/dna-switch-toehold-mediated-dna-isothermal-amplification-for-dengue-serotyping
#10
Soo Khim Chan, Akinori Kuzuya, Yee Siew Choong, Theam Soon Lim
The inherent ability of nucleic acids to recognize a complementary pair has gained wide popularity in DNA sensor applications. DNA molecules can be produced in bulk and easily incorporated with various nanomaterials for sensing applications. More complex designs and sophisticated DNA sensors have been reported over the years to allow DNA detection in a faster, cheaper, and more convenient manner. Here, we report a DNA sensor designed to function like a switch to turn "on" silver nanocluster (AgNC) generation in the presence of a specific DNA target...
July 31, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30011377/erratum
#11
(no author information available yet)
No abstract text is available yet for this article.
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30011241/homogeneous-btk-occupancy-assay-for-pharmacodynamic-assessment-of-tirabrutinib-gs-4059-ono-4059-target-engagement
#12
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...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29995453/first-nonphosphorylated-inhibitors-of-phosphoglucose-isomerase-identified-by-chemical-library-screening
#13
Sabrina G R Mota, Gustavo F Mercaldi, José G C Pereira, Paulo S L Oliveira, Ana Rodriguez, Artur T Cordeiro
Human African trypanosomiasis, Chagas disease, and leishmaniasis are human infections caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania. Besides their severity and global impact, treatments are still challenging. Currently available drugs have important limitations, highlighting the urgent need to develop new drugs. Phosphoglucose isomerase (PGI) is considered a promising target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29995452/development-and-characterization-of-quantitative-high-throughput-compatible-assays-for-proteolytic-degradation-of-glucagon
#14
Caitlin N Suire, Shelley Lane, Malcolm A Leissring
Glucagon is a vital peptide hormone involved in the regulation of blood sugar under fasting conditions. Although the processes underlying glucagon production and secretion are well understood, far less is known about its degradation, which could conceivably be manipulated pharmacologically for therapeutic benefit. We describe here the development of novel assays for glucagon degradation, based on fluoresceinated and biotinylated glucagon (FBG) labeled at the N- and C-termini, respectively. Proteolysis at any peptide bond within FBG separates the fluorescent label from the biotin tag, which can be quantified in multiple ways...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29991334/merits-and-pitfalls-in-the-characterization-of-covalent-inhibitors-of-bruton-s-tyrosine-kinase
#15
Christopher M Harris, Sage E Foley, Eric R Goedken, Mark Michalak, Sara Murdock, Noel S Wilson
In vitro analysis of covalent inhibitors requires special consideration, due to the time-dependent and typically irreversible nature of their target interaction. While many analyses are reported for the characterization of a final candidate, it is less clear which are most useful in the lead optimization phase of drug discovery. In the context of identifying covalent inhibitors of Bruton's tyrosine kinase (BTK), we evaluated multiple techniques for characterizing covalent inhibitors. Several methods qualitatively support the covalent mechanism of action or support a particular aspect of interaction but were not otherwise informative to differentiate inhibitors...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29991302/assay-for-detecting-g%C3%AE-i-mediated-decreases-in-camp-in-living-cells
#16
Paul Tewson, Scott Martinka, Nathan Shaner, Catherine Berlot, Anne Marie Quinn, Thomas Hughes
Cell-based assays to detect Gαi signaling are often indirect, frequently involve complex pharmacological interventions, and are usually blind to the kinetics of the signaling. Our goal was to develop a simple, direct measure of Gαi signaling in living cells. We previously reported our fluorescent cADDis assay and showed that it reliably detects Gαs-mediated increases in cAMP levels. Agonists that stimulate a Gs-coupled receptor produce changes in the intensity of bright green or red fluorescent protein sensors that can be followed over time using automated fluorescence plate readers or fluorescence imaging systems...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29991301/development-of-a-high-throughput-biochemical-assay-to-screen-for-inhibitors-of-aerobactin-synthetase-iuca
#17
Daniel C Bailey, Brian P Buckley, Mikhail V Chernov, Andrew M Gulick
Acquiring sufficient quantities of iron to support survival is often a critical limitation for pathogenic bacteria. To meet this demand, bacteria have evolved unique strategies to scavenge iron and circumvent the nutritional immunity exerted by their hosts. One common strategy, which is often a key virulence factor for bacterial pathogens, involves the synthesis, secretion, and reuptake of iron chelators known as siderophores. In vitro and in vivo studies have demonstrated that the siderophore aerobactin is critical for virulence in the hypervirulent pathotype of Klebsiella pneumoniae (hvKP)...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29969573/is-targeting-the-inflammasome-a-way-forward-for-neuroscience-drug-discovery
#18
Tessa Swanton, James Cook, James A Beswick, Sally Freeman, Catherine B Lawrence, David Brough
Neuroinflammation is becoming increasingly recognized as a critical factor in the pathology of both acute and chronic neurological conditions. Inflammasomes such as the one formed by NACHT, LRR, and PYD domains containing protein 3 (NLRP3) are key regulators of inflammation due to their ability to induce the processing and secretion of interleukin 1β (IL-1β). IL-1β has previously been identified as a potential therapeutic target in a variety of conditions due to its ability to promote neuronal damage under conditions of injury...
July 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29862873/clinical-trials-in-a-dish-a-perspective-on-the-coming-revolution-in-drug-development
#19
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
#20
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
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