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SLAS Discovery

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https://www.readbyqxmd.com/read/29768981/a-scalable-pipeline-for-high-throughput-flow-cytometry
#1
Aaron C Wilson, Ioannis K Moutsatsos, Gary Yu, Javier J Pineda, Yan Feng, Douglas S Auld
Flow cytometry (FC) provides high-content data for a variety of applications, including phenotypic analysis of cell surface and intracellular markers, characterization of cell supernatant or lysates, and gene expression analysis. Historically, sample preparation, acquisition, and analysis have presented as a bottleneck for running such types of assays at scale. This article will outline the solutions that have been implemented at Novartis which have allowed high-throughput FC to be successfully conducted and analyzed for a variety of cell-based assays...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29751735/identification-of-compounds-that-prolong-type-i-interferon-signaling-as-potential-vaccine-adjuvants
#2
Nikunj M Shukla, Kei-Ichiro Arimoto, Shiyin Yao, Jun-Bao Fan, Yue Zhang, Fumi Sato-Kaneko, Fitzgerald S Lao, Tadashi Hosoya, Karen Messer, Minya Pu, Howard B Cottam, Dennis A Carson, Tomoko Hayashi, Dong-Er Zhang, Maripat Corr
Vaccines are reliant on adjuvants to enhance the immune stimulus, and type I interferons (IFNs) have been shown to be beneficial in augmenting this response. We were interested in identifying compounds that would sustain activation of an endogenous type I IFN response as a co-adjuvant. We began with generation of a human monocytic THP-1 cell line with an IFN-stimulated response element (ISRE)-β-lactamase reporter construct for high-throughput screening. Pilot studies were performed to optimize the parameters and conditions for this cell-based Förster resonance energy transfer (FRET) reporter assay for sustaining an IFN-α-induced ISRE activation signal...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29750582/a-cytotoxic-three-dimensional-spheroid-high-throughput-assay-using-patient-derived-glioma-stem-cells
#3
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...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29746793/high-throughput-flow-cytometry-identifies-small-molecule-inhibitors-for-drug-repurposing-in-t-all
#4
Dominique R Perez, Christian K Nickl, Anna Waller, Cristina Delgado-Martin, Travis Woods, Nitesh D Sharma, Michelle L Hermiston, Mignon L Loh, Stephen P Hunger, Stuart S Winter, Alexandre Chigaev, Bruce Edwards, Larry A Sklar, Ksenia Matlawska-Wasowska
Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts...
May 1, 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
#5
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...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29724131/cycling-to-maintain-and-improve-fitness-line-1-modes-of-nuclear-entrance-and-retrotransposition
#6
Paolo Mita, Jef D Boeke
The LINE-1/L1 retrotransposon is a transposable element still active in the human genome. Most retrotransposons in the genome are inactive or repressed by several host mechanisms. In specific contexts, active L1 retrotransposons may evade repression and copy themselves into new genomic loci. Despite a general knowledge of the L1 life cycle, little was known about the dynamics of L1 proteins and function during the different stages of the host cell cycle. Our work highlighted a well-orchestrated localization of L1 proteins and mRNA that take advantage of mitotic nuclear membrane breakdown...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29699447/nuisance-compounds-pains-filters-and-dark-chemical-matter-in-the-gsk-hts-collection
#7
Subhas J Chakravorty, James Chan, Marie Nicole Greenwood, Ioana Popa-Burke, Katja S Remlinger, Stephen D Pickett, Darren V S Green, Martin C Fillmore, Tony W Dean, Juan I Luengo, Ricardo Macarrón
High-throughput screening (HTS) hits include compounds with undesirable properties. Many filters have been described to identify such hits. Notably, pan-assay interference compounds (PAINS) has been adopted by the community as the standard term to refer to such filters, and very useful guidelines have been adopted by the American Chemical Society (ACS) and subsequently triggered a healthy scientific debate about the pitfalls of draconian use of filters. Using an inhibitory frequency index, we have analyzed in detail the promiscuity profile of the whole GlaxoSmithKline (GSK) HTS collection comprising more than 2 million unique compounds that have been tested in hundreds of screening assays...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29689168/comparing-flow-cytometry-qbeads-plexscreen-assays-with-other-immunoassays-for-determining-multiple-analytes
#8
Mei Ding, Anders Cavallin, Nils-Olov Hermansson, Pia Berntsson, Lisa Jinton, Sandra Rodrigo Blomqvist
Immunoassays, utilizing the affinity of antibodies to their antigens, are powerful techniques and have been widely used for quantifying analytes, such as cytokines, in biological samples in the clinic and in drug discovery. Various immunoassays have been developed to fit for different purposes. Recently, bead-based flow cytometry assays have emerged as interesting options for multiplex quantification of analytes. In this study, we compared high-throughput flow cytometry multiplex iQue QBeads PlexScreen assays with several other commonly used immunoassays, including MSD, Luminex, ELISA, HTRF, and AlphaLISA assays...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29676938/the-development-of-a-biotinylated-nad-applied-human-poly-adp-ribose-polymerase-3-parp3-enzymatic-assay
#9
Ming Ji, Liyuan Wang, Nina Xue, Fangfang Lai, Sen Zhang, Jing Jin, Xiaoguang Chen
Poly(ADP-ribose) polymerase 3 (PARP3) is an important member of the PARP family and shares high structural similarities with both PARP1 and PARP2. The biological roles of PARP3 are currently under investigation; however, several key reports indicate the integral roles of PARP3 in DNA damage repair, and thus it has been investigated as a novel target in oncology. It is clear that the identification of selective PARP3 inhibitors would further advance the understanding of the biological roles of PARP3. Herein, we describe a modified PARP3 screening assay using biotinylated NAD+ as the specialized substrate...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29673279/advanced-development-of-primary-pancreatic-organoid-tumor-models-for-high-throughput-phenotypic-drug-screening
#10
Shurong Hou, Hervé Tiriac, Banu Priya Sridharan, Louis Scampavia, Franck Madoux, Jan Seldin, Glauco R Souza, Donald Watson, David Tuveson, Timothy P Spicer
Traditional high-throughput drug screening in oncology routinely relies on two-dimensional (2D) cell models, which inadequately recapitulate the physiologic context of cancer. Three-dimensional (3D) cell models are thought to better mimic the complexity of in vivo tumors. Numerous methods to culture 3D organoids have been described, but most are nonhomogeneous and expensive, and hence impractical for high-throughput screening (HTS) purposes. Here we describe an HTS-compatible method that enables the consistent production of organoids in standard flat-bottom 384- and 1536-well plates by combining the use of a cell-repellent surface with a bioprinting technology incorporating magnetic force...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29634393/high-throughput-flow-cytometric-method-for-the-simultaneous-measurement-of-car-t-cell-characterization-and-cytotoxicity-against-solid-tumor-cell-lines
#11
Emily M Martinez, Samuel D Klebanoff, Stephanie Secrest, Gabrielle Romain, Samuel T Haile, Peter C R Emtage, Amy E Gilbert
High-throughput flow cytometry is an attractive platform for the analysis of adoptive cellular therapies such as chimeric antigen receptor T cell therapy (CAR-T) because it allows for the concurrent measurement of T cell-dependent cellular cytotoxicity (TDCC) and the functional characterization of engineered T cells with respect to percentage of CAR transduction, T cell phenotype, and measurement of T cell function such as activation in a single assay. The use of adherent tumor cell lines can be challenging in these flow-based assays...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29630847/screening-for-inhibitors-of-acetaldehyde-dehydrogenase-adhe-from-enterohemorrhagic-escherichia-coli-ehec
#12
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...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29608398/a-high-throughput-flow-cytometry-screen-identifies-molecules-that-inhibit-hantavirus-cell-entry
#13
Tione Buranda, Catherine Gineste, Yang Wu, Virginie Bondu, Dominique Perez, Kaylin R Lake, Bruce S Edwards, Larry A Sklar
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), which infects more than 200,000 people worldwide. Sin Nombre virus (SNV) and Andes virus (ANDV) cause the most severe form of HCPS, with case fatality ratios of 30%-40%. There are no specific therapies or vaccines for SNV. Using high-throughput flow cytometry, we screened the Prestwick Chemical Library for small-molecule inhibitors of the binding interaction between UV-inactivated and fluorescently labeled SNVR18 particles, and decay-accelerating factor (DAF) expressed on Tanoue B cells...
April 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29608391/a-fragment-library-screening-approach-to-identify-selective-inhibitors-against-an-essential-fungal-enzyme
#14
Gopal P Dahal, Ronald E Viola
Pathogenic fungi represent a growing threat to human health, with an increase in the frequency of drug-resistant fungal infections. Identifying targets from among the selected metabolic pathways that are unique to microbial species presents an opportunity to develop new antifungal agents against new and untested targets to combat this growth threat. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in a uniquely microbial amino acid biosynthetic pathway and is essential for microbial viability...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29562800/discovery-of-small-molecule-antagonists-of-the-h3k9me3-binding-to-uhrf1-tandem-tudor-domain
#15
Guillermo Senisterra, Hugh Y Zhu, Xiao Luo, Hailong Zhang, Guoliang Xun, Chunliang Lu, Wen Xiao, Taraneh Hajian, Peter Loppnau, Irene Chau, Fengling Li, Abdellah Allali-Hassani, Peter Atadja, Counde Oyang, En Li, Peter J Brown, Cheryl H Arrowsmith, Kehao Zhao, Zhengtian Yu, Masoud Vedadi
Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29547351/plate-based-phenotypic-screening-for-pain-using-human-ipsc-derived-sensory-neurons
#16
Peter Stacey, Anne Mai Wassermann, Laura Kammonen, Emma Impey, Anna Wilbrey, Darren Cawkill
Screening against a disease-relevant phenotype to identify compounds that change the outcome of biological pathways, rather than just the activity of specific targets, offers an alternative approach to find modulators of disease characteristics. However, in pain research, use of in vitro phenotypic screens has been impeded by the challenge of sourcing relevant neuronal cell types in sufficient quantity and developing functional end-point measurements with a direct disease link. To overcome these hurdles, we have generated human induced pluripotent stem cell (hiPSC)-derived sensory neurons at a robust production scale using the concept of cryopreserved "near-assay-ready" cells to decouple complex cell production from assay development and screening...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29543559/spontaneous-glioblastoma-spheroid-infiltration-of-early-stage-cerebral-organoids-models-brain-tumor-invasion
#17
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)...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29537924/fragment-screening-of-human-kynurenine-aminotransferase-ii
#18
Gayan S Jayawickrama, Alireza Nematollahi, Guanchen Sun, W Bret Church
Kynurenine aminotransferase-II (KAT-II) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that acts in the tryptophan metabolic pathway by catalyzing the transamination of kynurenine into kynurenic acid (KYNA). It is one of four isoforms in the KAT family, of which it is the primary homologue responsible for KYNA production in the mammalian brain. KAT-II is targeted for inhibition as KYNA is implicated in diseases such as schizophrenia, where it is found in elevated concentrations. Previously, many different approaches have been taken to develop KAT-II inhibitors, and herein fragment-based drug design (FBDD) approaches have been exploited to provide further lead compounds that can be designed into novel inhibitors...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29533733/%C3%AE-f508-cftr-modulator-screen-based-on-cell-surface-targeting-of-a-chimeric-nucleotide-binding-domain-1-reporter
#19
Puay-Wah Phuan, Guido Veit, Joseph-Anthony Tan, Ariel Roldan, Walter E Finkbeiner, Peter M Haggie, Gergely L Lukacs, Alan S Verkman
The most common cystic fibrosis-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of phenylalanine at residue 508 (∆F508). The ∆F508 mutation impairs folding of nucleotide binding domain 1 (NBD1) and interfacial interactions of NBD1 and the membrane spanning domains. Here, we report a domain-targeted screen to identify ∆F508-CFTR modulators that act on NBD1. A biochemical screen for ΔF508-NBD1 cell surface expression was done in Madin-Darby canine kidney cells expressing a chimeric reporter consisting of ΔF508-NBD1, the CD4 transmembrane domain, and an extracellular horseradish peroxidase (HRP) reporter...
March 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29522699/statistical-behaviors-personal-and-computer-aided-observations
#20
James A Hanley
My early years as a statistician were with the Eastern Co-operative Oncology Group and the Radiation Oncology Therapy Group; three of these years were spent at the Sidney Farber Cancer Institute. Later, I collaborated widely with investigators in many clinical research areas. I reflect on the "statistical interrogations of nature" I saw (and helped some of these) investigators plan and carry out. I look back on their (and my own) statistical behaviors when interpreting the information these interrogations produced and-using a few vignettes and some computer-generated observations-draw some lessons from them...
March 1, 2018: SLAS Discovery
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