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SLAS Discovery

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https://www.readbyqxmd.com/read/30011377/erratum
#1
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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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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/29958052/identification-of-cosalane-as-an-inhibitor-of-human-and-murine-cc-chemokine-receptor-7-signaling-via-a-high-throughput-screen
#9
Emily A Hull-Ryde, Melissa A Porter, Kenneth A Fowler, Dmitri Kireev, Kelin Li, Catherine D Simpson, Maria F Sassano, Mark J Suto, Kenneth H Pearce, William Janzen, James M Coghill
CC-chemokine receptor 7 (CCR7) is a G protein-coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states. Due to its therapeutic relevance and absence of available CCR7 inhibitors, we undertook a high-throughput screen (HTS) to identify small-molecule antagonists of the receptor. Here, we describe a robust HTS approach using a commercially available β-galactosidase enzyme fragment complementation system and confirmatory transwell chemotaxis assays...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29932789/development-of-a-broadly-applicable-assay-for-measurement-of-glycan-directed-enzymatic-activity
#10
Alberto Bresciani, Ottavia Cecchetti, Antonino Missineo, Pier Giorgio Pacifici, Licia Tomei, Steven Rodems
Glycosylation is a key posttranslational modification that tags protein to membranes, organelles, secretory pathways, and degradation. Aberrant protein glycosylation is present both in acquired diseases, such as cancer and neurodegeneration, and in congenital disorders of glycosylation (CDGs). Consequently, the ability to interrogate the activity of enzymes that can modify protein glycan moieties is key for drug discovery projects aimed at finding modulators of these enzymes. To date, low-throughput technologies such as SDS-PAGE and mass spectrometry have been used, which are not suitable for compound screening in drug discovery...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29898642/a-novel-multiple-read-screen-for-metabolically-active-compounds-based-on-a-genetically-encoded-fret-sensor-for-atp
#11
Ziyan Zhao, Rahul Rajagopalan, Adam Zweifach
Both glycolysis and mitochondrial energetics are targets of interest for developing antiproliferative cancer therapeutics. We developed a novel multiple-read assay based on long-term expression in K562 cells of a genetically encoded intramolecular Förster resonance energy transfer sensor for adenosine triphosphate (ATP). The assay, conducted in a fluorescent plate reader, can identify compounds that inhibit oxidative phosphorylation-dependent ATP production, glycolysis, or both after short-term treatment. We screened a National Cancer Institute (NCI) compound library, identifying inhibitors of oxidative phosphorylation-dependent ATP production and glycolysis...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29898633/automated-high-throughput-flow-cytometry-for-high-content-screening-in-antibody-development
#12
Yana Wang, Tomoki Yoshihara, Samson King, Tinh Le, Patrick Leroy, Xiansi Zhao, Ching Kit Chan, Zhong-Hua Yan, Saurabh Menon
The tedious sample preparation for flow cytometry limits the throughput and thus its usage as a primary screening method despite its sensitivity and accuracy. With the growing focus on utilizing antibodies as a therapeutic modality in drug discovery, it is critical to develop a high-throughput flow cytometry (HTFC) workflow to cope with the increasing need to support antibody discovery programs. We have developed a seamless HTFC sample preparation and readout workflow using the HighRes modular robotic system and the IntelliCyt iQue Screener PLUS...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29884090/repurposing-a-histamine-detection-platform-for-high-throughput-screening-of-histidine-decarboxylase
#13
Yu-Chi Juang, Xavier Fradera, Yongxin Han, Anthony William Partridge
Histidine decarboxylase (HDC) is the primary enzyme that catalyzes the conversion of histidine to histamine. HDC contributes to many physiological responses as histamine plays important roles in allergic reaction, neurological response, gastric acid secretion, and cell proliferation and differentiation. Small-molecule modulation of HDC represents a potential therapeutic strategy for a range of histamine-associated diseases, including inflammatory disease, neurological disorders, gastric ulcers, and select cancers...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29874524/integration-of-lead-discovery-tactics-and-the-evolution-of-the-lead-discovery-toolbox
#14
Melanie Leveridge, Chun-Wa Chung, Jeffrey W Gross, Christopher B Phelps, Darren Green
There has been much debate around the success rates of various screening strategies to identify starting points for drug discovery. Although high-throughput target-based and phenotypic screening has been the focus of this debate, techniques such as fragment screening, virtual screening, and DNA-encoded library screening are also increasingly reported as a source of new chemical equity. Here, we provide examples in which integration of more than one screening approach has improved the campaign outcome and discuss how strengths and weaknesses of various methods can be used to build a complementary toolbox of approaches, giving researchers the greatest probability of successfully identifying leads...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29865911/a-multiplexed-screening-assay-to-evaluate-chemotherapy-induced-myelosuppression-using-healthy-peripheral-blood-and-bone-marrow
#15
Komal K Javarappa, Dimitrios Tsallos, Caroline A Heckman
Myelosuppression is a major side effect of chemotherapy in cancer patients and can result in infections, bleeding complications, and increased risk of morbidity and mortality, as well as limit the drug dose and frequency of administration. Chemotherapy-induced myelosuppression is caused by the disruption of normal hematopoiesis. Thus, prior understanding of the adverse effects of chemotherapies on hematopoietic cells is essential to minimize the side effects of cancer treatment. Traditional methods such as colony-forming assays for studying chemotherapy-induced myelosuppression are time-consuming and labor intensive...
June 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29884089/a-multiplexed-assay-that-monitors-effects-of-multiple-compound-treatment-times-reveals-candidate-immune-enhancing-compounds
#16
Ziyan Zhao, Liza Henowitz, Adam Zweifach
We previously developed a flow cytometry assay that monitored lytic granule exocytosis in cytotoxic T lymphocytes stimulated by contacting beads coated with activating anti-CD3 antibodies. That assay was multiplexed in that responses of cells that did or did not receive the activating stimulus were distinguished via changes in light scatter accompanying binding of cells to beads, allowing us to discriminate compounds that activate responses on their own from compounds that enhance responses in cells that received the activating stimulus, all within a single sample...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29873570/miniaturized-high-throughput-multiparameter-flow-cytometry-assays-measuring-in-vitro-human-dendritic-cell-maturation-and-t-cell-activation-in-mixed-lymphocyte-reactions
#17
Yi Fan, Joseph G Naglich, Jennifer D Koenitzer, Humberto Ribeiro, Jonathan Lippy, Jordan Blum, Xin Li, Christina Milburn, Bryan Barnhart, Litao Zhang, Mark P Fereshteh
Enhancing antitumor activities of the human immune system is a clinically proven approach with the advent of monoclonal antibodies recognizing programmed cell death protein-1 (PD1) receptors on immune cell surfaces. Historically, using flow cytometry as a means to assess next-generation agent activities was underused, largely due to limits on cell number and assay sensitivity. Here, we leveraged an IntelliCyt high-throughput flow cytometry platform to monitor human dendritic cell maturation and lymphocyte proliferation in mixed lymphocyte reactions...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29862873/clinical-trials-in-a-dish-a-perspective-on-the-coming-revolution-in-drug-development
#18
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...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29852084/expediting-antibody-discovery-with-a-cell-and-bead-multiplexed-competition-assay
#19
Zhaoping Liu, John O'Rourke
With advances in molecular engineering and humanization, monoclonal antibodies are one of the fastest-growing classes of biopharmaceuticals. During antibody discovery, antibody from hybridoma or primary B-cell supernatants is screened for the desired binding characteristics, and secondary screens measure antibody function and concentration, identify immunoglobulin G (IgG) isotype, and assess cell health. In order to expedite the antibody discovery process, we developed a high-throughput, multiplexed cell and bead-based competition assay that identifies and quantitates mouse IgG isotypes and assesses cell health...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29852073/application-of-native-esi-ms-to-characterize-interactions-between-compounds-derived-from-fragment-based-discovery-campaigns-and-two-pharmaceutically-relevant-proteins
#20
Agni F M Gavriilidou, Finn P Holding, Joseph E Coyle, Renato Zenobi
Native electrospray ionization mass spectrometry (ESI-MS) was applied to analyze the binding of compounds generated during fragment-based drug discovery (FBDD) campaigns against two functionally distinct proteins, the X-linked inhibitor of apoptosis protein (XIAP) and cyclin-dependent kinase 2 (CDK2). Compounds of different molecular weights and a wide range of binding affinities obtained from the hits to leads and lead optimization stages of FBDD campaigns were studied, and their dissociation constants (Kd ) were measured by native ESI-MS...
May 1, 2018: SLAS Discovery
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