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SLAS Discovery

Il Doh, Yong-Jun Kwon, Bosung Ku, Dong Woo Lee
Hepatocellular carcinoma (HCC), a major histological subtype of liver cancer, is the third most common cause of cancer-related death worldwide. Currently, many curative standard treatments using target-specific chemotherapeutic agents are being developed. However, drug efficacy tests based on the 2D monolayer cell culture model do not effectively screen the best drug candidates because they do not accurately reflect in vivo tumor microenvironments. Thus, to select the best drug candidates or repositioning drugs, we developed new 3D in vitro hepatic tumor models, including 3D forming and preformed sphere models...
February 12, 2019: SLAS Discovery
Po-Hsien Lee, Xi Xiao Huang, Bin Tean Teh, Ley-Moy Ng
Thermal shift assay (TSA) is an increasingly popular technique used for identifying protein stabilizing conditions or interacting ligands in X-ray crystallography and drug discovery applications. Although the setting up and running of TSA reactions is a relatively simple process, the subsequent analysis of TSA data, especially in high-throughput format, requires substantial amount of effort if conducted manually. We therefore developed the Thermal Shift Assay-Curve Rapid and Automatic Fitting Tool (TSA-CRAFT), a freely available software that enable automatic analysis of TSA data of any throughput...
February 11, 2019: SLAS Discovery
Scott J Warchal, John C Dawson, Neil O Carragher
Multiparametric high-content imaging assays have become established to classify cell phenotypes from functional genomic and small-molecule library screening assays. Several groups have implemented machine learning classifiers to predict the mechanism of action of phenotypic hit compounds by comparing the similarity of their high-content phenotypic profiles with a reference library of well-annotated compounds. However, the majority of such examples are restricted to a single cell type often selected because of its suitability for simple image analysis and intuitive segmentation of morphological features...
January 29, 2019: SLAS Discovery
Erika Wiseman, Annj Zamuner, Zuming Tang, James Rogers, Sabrina Munir, Lucy Di Silvio, Davide Danovi, Lorenzo Veschini
Endothelial cells (ECs) are widely heterogeneous at the cell level and serve different functions at the vessel and tissue levels. EC-forming colonies derived from induced pluripotent stem cells (iPSC-ECFCs) alongside models such as primary human umbilical vein ECs (HUVECs) are slowly becoming available for research with future applications in cell therapies, disease modeling, and drug discovery. We and others previously described high-content analysis approaches capturing unbiased morphology-based measurements coupled with immunofluorescence and used these for multidimensional reduction and population analysis...
January 25, 2019: SLAS Discovery
Vytaute Starkuviene, Stefan M Kallenberger, Nina Beil, Tautvydas Lisauskas, Bastian So-Song Schumacher, Ruben Bulkescher, Piotr Wajda, Manuel Gunkel, Jürgen Beneke, Holger Erfle
Due to high associated costs and considerable time investments of cell-based screening, there is a strong demand for new technologies that enable preclinical development and tests of diverse biologicals in a cost-saving and time-efficient manner. For those reasons we developed the high-density cell array (HD-CA) platform, which miniaturizes cell-based screening in the form of preprinted and ready-to-run screening arrays. With the HD-CA technology, up to 24,576 samples can be tested in a single experiment, thereby saving costs and time for microscopy-based screening by 75%...
January 25, 2019: SLAS Discovery
Pierre Baillargeon, Virneliz Fernandez-Vega, Banu Priya Sridharan, Steven Brown, Patrick R Griffin, Hugh Rosen, Benjamin Cravatt, Louis Scampavia, Timothy P Spicer
The Scripps Research Molecular Screening Center (SRMSC) was founded in 2004 and comprises more than $22 million of specialized automation. As part of the Translational Research Institute (TRI), it comprises early drug discovery labs and medicinal chemistry. Together with Scripps Research at the La Jolla, California, campus, this represents one of the most competitive academic industrial screening centers worldwide. The SRMSC uses automated platforms, one a screening cell and the other a cherry-picking platform...
January 25, 2019: SLAS Discovery
Reka A Otvos, Kristina B M Still, Govert W Somsen, August B Smit, Jeroen Kool
Natural extracts are complex mixtures that may be rich in useful bioactive compounds and therefore are attractive sources for new leads in drug discovery. This review describes drug discovery from natural products and in explaining this process puts the focus on ion-channel drug discovery. In particular, the identification of bioactives from natural products targeting nicotinic acetylcholine receptors (nAChRs) and serotonin type 3 receptors (5-HT3 Rs) is discussed. The review is divided into three parts: "Targets," "Sources," and "Approaches...
January 25, 2019: SLAS Discovery
Raimo Franke, Bettina Hinkelmann, Verena Fetz, Theresia Stradal, Florenz Sasse, Frank Klawonn, Mark Brönstrup
Mode of action (MoA) identification of bioactive compounds is very often a challenging and time-consuming task. We used a label-free kinetic profiling method based on an impedance readout to monitor the time-dependent cellular response profiles for the interaction of bioactive natural products and other small molecules with mammalian cells. Such approaches have been rarely used so far due to the lack of data mining tools to properly capture the characteristics of the impedance curves. We developed a data analysis pipeline for the xCELLigence Real-Time Cell Analysis detection platform to process the data, assess and score their reproducibility, and provide rank-based MoA predictions for a reference set of 60 bioactive compounds...
January 25, 2019: SLAS Discovery
Alexander Kensert, Philip J Harrison, Ola Spjuth
The quantification and identification of cellular phenotypes from high-content microscopy images has proven to be very useful for understanding biological activity in response to different drug treatments. The traditional approach has been to use classical image analysis to quantify changes in cell morphology, which requires several nontrivial and independent analysis steps. Recently, convolutional neural networks have emerged as a compelling alternative, offering good predictive performance and the possibility to replace traditional workflows with a single network architecture...
January 14, 2019: SLAS Discovery
Antje Janosch, Carolin Kaffka, Marc Bickle
Phenotypic screens using automated microscopy allow comprehensive measurement of the effects of compounds on cells due to the number of markers that can be scored and the richness of the parameters that can be extracted. The high dimensionality of the data is both a rich source of information and a source of noise that might hide information. Many methods have been proposed to deal with this complex data in order to reduce the complexity and identify interesting phenotypes. Nevertheless, the majority of laboratories still only use one or two parameters in their analysis, likely due to the computational challenges of carrying out a more sophisticated analysis...
January 7, 2019: SLAS Discovery
Philip Brennecke, Dace Rasina, Oscar Aubi, Katja Herzog, Johannes Landskron, Bastien Cautain, Francisca Vicente, Jordi Quintana, Jordi Mestres, Bahne Stechmann, Bernhard Ellinger, Jose Brea, Jacek L Kolanowski, Radosław Pilarski, Mar Orzaez, Antonio Pineda-Lucena, Luca Laraia, Faranak Nami, Piotr Zielenkiewicz, Kamil Paruch, Espen Hansen, Jens P von Kries, Martin Neuenschwander, Edgar Specker, Petr Bartunek, Sarka Simova, Zbigniew Leśnikowski, Stefan Krauss, Lari Lehtiö, Ursula Bilitewski, Mark Brönstrup, Kjetil Taskén, Aigars Jirgensons, Heiko Lickert, Mads H Clausen, Jeanette H Andersen, Maria J Vicent, Olga Genilloud, Aurora Martinez, Marc Nazaré, Wolfgang Fecke, Philip Gribbon
Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data...
January 7, 2019: SLAS Discovery
Dennis J Colussi, Marlene A Jacobson
Tay-Sachs disease is an inherited lysosomal storage disease resulting from mutations in the lysosomal enzyme, β-hexosaminidase A, and leads to excessive accumulation of GM2 ganglioside. Tay-Sachs patients with the infantile form do not live beyond 2-4 years of age due to rapid, progressive neurodegeneration. Enzyme replacement therapy is not a therapeutic option due to its inability to cross the blood-brain barrier. As an alternative, small molecules identified from high-throughput screening could provide leads suitable for chemical optimization to target the central nervous system...
January 7, 2019: SLAS Discovery
Vito Giuseppe D'Agostino, Denise Sighel, Chiara Zucal, Isabelle Bonomo, Mariachiara Micaelli, Graziano Lolli, Alessandro Provenzani, Alessandro Quattrone, Valentina Adami
RNA-binding proteins (RBPs) are pleiotropic factors that control the processing and functional compartmentalization of transcripts by binding primarily to mRNA untranslated regions (UTRs). The competitive and/or cooperative interplay between RBPs and an array of coding and noncoding RNAs (ncRNAs) determines the posttranscriptional control of gene expression, influencing protein production. Recently, a variety of well-recognized and noncanonical RBP domains have been revealed by modern system-wide analyses, underlying an evolving classification of ribonucleoproteins (RNPs) and their importance in governing physiological RNA metabolism...
January 7, 2019: SLAS Discovery
Ashwini K Devkota, John R Veloria, Hou-Fu Guo, Jonathan M Kurie, Eun Jeong Cho, Kevin N Dalby
Lysyl hydroxylase-2 (LH2) catalyzes the hydroxylation of telopeptidyl lysine residues on collagen, leading to the formation of stable collagen cross-links that connect collagen molecules and stabilize the extracellular matrix. High levels of LH2 have been reported in the formation and stabilization of hydroxylysine aldehyde-derived collagen cross-links (HLCCs), leading to fibrosis and cancer metastasis in certain tissues. Identification of small-molecule inhibitors targeting LH2 activity requires a robust and suitable assay system, which is currently lacking...
December 27, 2018: SLAS Discovery
Sanjay J Danthi, Beirong Liang, Oanh Smicker, Benjamin Coupland, Jill Gregory, Estelle Gefteas, Drew Tietz, Helen Klodnitsky, Kristen Randall, Adam Belanger, Theresa A Kuntzweiler
SLC6A19 (B0 AT1) is a neutral amino acid transporter, the loss of function of which results in Hartnup disease. SLC6A19 is also believed to have an important role in amino acid homeostasis, diabetes, and weight control. A small-molecule inhibitor of human SLC6A19 (hSLC6A19) was identified using two functional cell-based assays: a fluorescence imaging plate reader (FLIPR) membrane potential (FMP) assay and a stable isotope-labeled neutral amino acid uptake assay. A diverse collection of 3440 pharmacologically active compounds from the Microsource Spectrum and Tocriscreen collections were tested at 10 µM in both assays using MDCK cells stably expressing hSLC6A19 and its obligatory subunit, TMEM27...
December 27, 2018: SLAS Discovery
Joseph Shaw, Ian Dale, Paul Hemsley, Lindsey Leach, Nancy Dekki, Jonathan P Orme, Verity Talbot, Ana J Narvaez, Michal Bista, Daniel Martinez Molina, Michael Dabrowski, Martin J Main, Davide Gianni
Methods to measure cellular target engagement are increasingly being used in early drug discovery. The Cellular Thermal Shift Assay (CETSA) is one such method. CETSA can investigate target engagement by measuring changes in protein thermal stability upon compound binding within the intracellular environment. It can be performed in high-throughput, microplate-based formats to enable broader application to early drug discovery campaigns, though high-throughput forms of CETSA have only been reported for a limited number of targets...
December 13, 2018: SLAS Discovery
Monika I Konaklieva
Over the past century, a multitude of derivatives of structural scaffolds with established antimicrobial potential have been prepared and tested, and a variety of new scaffolds have emerged. The effectiveness of antibiotics, however, is in sharp decline because of the emergence of drug-resistant microorganisms. The prevalence of drug resistance, both in clinical and community settings, is a consequence of bacterial ingenuity in altering pathways and/or cell morphology, making it a persistent threat to human health...
December 7, 2018: SLAS Discovery
Wataru Asano, Yu Takahashi, Motoaki Kawano, Yoshiji Hantani
Peripheral arterial disease (PAD) is an occlusive disease that can lead to atherosclerosis. The involvement of arginase II (Arg II) in PAD progression has been proposed. However, no promising drugs targeting Arg II have been developed to date for the treatment of PAD. In this study, we established a method for detecting the activity of Arg II via high-throughput label-free RapidFire mass spectrometry using hydrophilic interaction chromatography, which enables the direct measurement of l-ornithine produced by Arg II...
December 7, 2018: SLAS Discovery
Lorena Pochini, Michele Galluccio, Mariafrancesca Scalise, Lara Console, Cesare Indiveri
OCTN is a small subfamily of membrane transport proteins that belongs to the larger SLC22 family. Two of the three members of the subfamily, namely, OCTN2 and OCTN1, are present in humans. OCTN2 plays a crucial role in the absorption of carnitine from diet and in its distribution to tissues, as demonstrated by the occurrence of severe pathologies caused by malfunctioning or altered expression of this transporter. These findings suggest avoiding a strict vegetarian diet during pregnancy and in childhood. Other roles of OCTN2 are related to the traffic of carnitine derivatives in many tissues...
December 7, 2018: SLAS Discovery
David A Close, Allen Xinwei Wang, Stanton J Kochanek, Tongying Shun, Julie L Eiseman, Paul A Johnston
Animal and clinical studies demonstrate that cancer drug combinations (DCs) are more effective than single agents. However, it is difficult to predict which DCs will be more efficacious than individual drugs. Systematic DC high-throughput screening (HTS) of 100 approved drugs in the National Cancer Institute's panel of 60 cancer cell lines (NCI-60) produced data to help select DCs for further consideration. We miniaturized growth inhibition assays into 384-well format, increased the fetal bovine serum amount to 10%, lengthened compound exposure to 72 h, and used a homogeneous detection reagent...
November 30, 2018: SLAS Discovery
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