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Development of a high-throughput screening platform to identify new therapeutic agents for Medulloblastoma Group 3 SLAS Discov. (IF 3.1) Pub Date : 2024-02-12 Inés Fallon, Henar Hernando, Olga Almacellas-Rabaiget, Berta Marti-Fuster, Cesare Spadoni, Darell D Bigner, Eva Méndez
Pediatric brain tumors (PBTs) represent about 25% of all pediatric cancers and are the most common solid tumors in children and adolescents. Medulloblastoma (MB) is the most frequently occurring malignant PBT, accounting for almost 10% of all pediatric cancer deaths. MB Group 3 (MB G3) accounts for 25-30% of all MB cases and has the worst outcome, particularly when associated with MYC amplification
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The openOCHEM consensus model is the best-performing open-source predictive model in the First EUOS/SLAS joint compound solubility challenge SLAS Discov. (IF 3.1) Pub Date : 2024-02-03 Andrea Hunklinger, Peter Hartog, Martin Šícho, Guillaume Godin, Igor V. Tetko
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Perspectives on phenotypic screening−Screen Design and Assay Technology Special Interest Group SLAS Discov. (IF 3.1) Pub Date : 2024-02-02 Chorom Pak, Kaylene J. Simpson, Andrea D. Weston, Mary Ellen Cvijic, Kenda Evans, Andrew D. Napper
Here we offer perspectives on phenotypic screening based on a wide-ranging discussion entitled “Phenotypic screening, target ID, and multi-omics: enabling more disease relevance in early discovery?” at the Screen Design and Assay Technology Special Interest Group Meeting at the 2023 SLAS Conference. During the session, the authors shared their own experience from within their respective organizations
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Activity and inhibition of the SARS-CoV-2 Omicron nsp13 R392C variant using RNA duplex unwinding assays SLAS Discov. (IF 3.1) Pub Date : 2024-02-01 Nicole L. Inniss, Margarita Rzhetskaya, Ted Ling-Hu, Ramon Lorenzo-Redondo, Kelly E. Bachta, Karla J.F. Satchell, Judd F. Hultquist
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3D-Suspension Culture Platform for High Throughput Screening of Neurotoxic Chemicals Using LUHMES Dopaminergic Neurons SLAS Discov. (IF 3.1) Pub Date : 2024-01-26 Zhi-Bin Tong, Ruili Huang, John Braisted, Pei-Hsuan Chu, Anton Simeonov, David L. Gerhold
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Covalent hits and where to find them SLAS Discov. (IF 3.1) Pub Date : 2024-01-25 Simon C.C. Lucas, J. Henry Blackwell, Sarah H. Hewitt, Hannah Semple, Benjamin C. Whitehurst, Hua Xu
Covalent hits for drug discovery campaigns are neither fantastic beasts nor mythical creatures, they can be routinely identified through electrophile-first screening campaigns using a suite of different techniques. These include biophysical and biochemical methods, cellular approaches, and DNA-encoded libraries. Employing best practice, however, is critical to success. The purpose of this review is
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Protocol for High Throughput 3D Drug Screening of Patient Derived Melanoma and Renal Cell Carcinoma SLAS Discov. (IF 3.1) Pub Date : 2024-01-11 Luis M. Ortiz Jordan, Virneliz Fernández Vega, Justin Shumate, Adam Peles, Jordan Zeiger, Louis Scampavia, Timothy P. Spicer
High Throughput Screening (HTS) with 3D cell models is possible thanks to the recent progress and development in 3D cell culture technologies. Results from multiple studies have demonstrated different drug responses between 2D and 3D cell culture. It is now widely accepted that 3D cell models more accurately represent the physiologic conditions of tumors over 2D cell models. However, there is still
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Developing Recombinant Antibodies by Phage Display Technology to Neutralize Viral Infectious Diseases SLAS Discov. (IF 3.1) Pub Date : 2024-01-03 Mujahed I. Mustafa, Ahmed Mohammed
The use of recombinant antibodies developed through phage display technology offers a promising approach for combating viral infectious diseases. By specifically targeting antigens on viral surfaces, these antibodies have the potential to reduce the severity of infections or even prevent them altogether. With the emergence of new and more virulent strains of viruses, it is crucial to develop innovative
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Micro/nano topological modification of TiO2 nanotubes activates Thy-1 signaling to control osteogenic differentiation of stem cells SLAS Discov. (IF 3.1) Pub Date : 2023-12-31 Li Jinsheng, Deng Qing, Chen Junhao, Si Qiqi, Chen Jieru, Yang Liwen, Guo Zhiyun, Guo Tailin, Weng Jie
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FLECS Technology for High-Throughput Screening of Hypercontractile Cellular Phenotypes in Fibrosis: A Function-First Approach to Anti-Fibrotic Drug Discovery SLAS Discov. (IF 3.1) Pub Date : 2023-12-28 Yao Wang, Enrico Cortes, Ricky Huang, Jeremy Wan, Junyi Zhao, Boris Hinz, Robert Damoiseaux, Ivan Pushkarsky
The pivotal role of myofibroblast contractility in the pathophysiology of fibrosis is widely recognized, yet HTS approaches are not available to quantify this critically important function in drug discovery. We developed, validated, and scaled-up a HTS platform that quantifies contractile function of primary human lung myofibroblasts upon treatment with pro-fibrotic TGF-β1. With the fully automated
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Establishment of a high-content imaging assay for tau aggregation in hiPSC-derived neurons differentiated from two protocols to routinely evaluate compounds and genetic perturbations. SLAS Discov. (IF 3.1) Pub Date : 2023-12-19 Lamiaa Bahnassawy, Nathalie Nicolaisen, Christopher Untucht, Benjamin Mielich-Süss, Lydia Reinhardt, Janina S. Ried, Martina P. Morawe, Daniela Geist, Anja Finck, Elke Käfer, Jürgen Korffmann, Matthew Townsend, Brinda Ravikumar, Viktor Lakics, Miroslav Cik, Peter Reinhardt
Aberrant protein aggregation is a pathological cellular hallmark of many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), where the tau protein is aggregating, forming neurofibrillary tangles (NFTs), and propagating from neuron to neuron. These processes have been linked to disease progression and a decline in cognitive function. Various therapeutic approaches
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Screening for molecular glues – challenges and opportunities SLAS Discov. (IF 3.1) Pub Date : 2023-12-15 Geoffrey A. Holdgate, Catherine Bardelle, Sophia K. Berry, Alice Lanne, Maria Emanuela Cuomo
Molecular glues are small molecules, typically smaller than PROTACs, and usually with improved physicochemical properties that aim to stabilise the interaction between two proteins. Most often this approach is used to improve or induce an interaction between the target and an E3 ligase, but other interactions which stabilise interactions to increase activity or to inhibit binding to a natural effector
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Protocol for 3D Drug Sensitivity and Resistance Testing of Patient-Derived Cancer Cells in 384-Well Plates SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 Michaela Feodoroff, Piia Mikkonen, Mariliina Arjama, Astrid Murumägi, Olli Kallioniemi, Swapnil Potdar, Laura Turunen, Vilja Pietiäinen
Establishment of drug testing of patient-derived cancer cells (PDCs) in physiologically relevant 3-dimensional (3D) culture is central for drug discovery and cancer research, as well as for functional precision medicine. Here, we describe the detailed protocol allowing the 3D drug testing of PDCs – or any type of cells of interest – in Matrigel in 384-well plate format using automation. We also provide
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Ex Vivo Discovery of Synergistic Drug Combinations for Hematologic Malignancies SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 Kamran A. Ali, Reecha D. Shah, Anukriti Dhar, Nina M. Myers, Cameron Nguyen, Arisa Paul, Jordan E. Mancuso, A. Scott Patterson, James P. Brody, Diane Heiser
Combination therapies have improved outcomes for patients with acute myeloid leukemia (AML). However, these patients still have poor overall survival. Although many combination therapies are identified with high-throughput screening (HTS), these approaches are constrained to disease models that can be grown in large volumes (e.g., immortalized cell lines), which have limited translational utility.
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Quantitative target engagement of RIPK1 in human whole blood via the cellular thermal shift assay for potential pre-clinical and clinical applications SLAS Discov. (IF 3.1) Pub Date : 2023-12-14 Shitalben Patel, Marie Karlsson, Joseph T. Klahn, Frank Gambino, Helena Costa, Kathleen A. McGuire, Christina K. Baumgartner, Jon Williams, Sarah Sandoz, James E. Kath
The cellular thermal shift assay (CETSA®) is a target engagement method widely used for preclinical characterization of small molecule compounds. CETSA® has been used for semi-quantitative readouts in whole blood with PBMC isolation, and quantitative, plate-based readouts using cell lines. However, there has been no quantitative evaluation of CETSA® in unprocessed human whole blood, which is preferred
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In Vitro Three-dimensional (3D) Cell Culture Tools for Spheroid and Organoid Models SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 Sang-Yun Lee, In-Seong Koo, Hyun Ju Hwang, Dong Woo Lee
Three-dimensional (3D) cell culture technology has been steadily studied since the 1990’s due to its superior biocompatibility compared to the conventional two-dimensional (2D) cell culture technology, and has recently developed into an organoid culture technology that further improved biocompatibility. Since the 3D culture of human cell lines in artificial scaffolds was demonstrated in the early 90′s
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Patient derived glioma stem cell spheroid reporter assays for live cell high content analysis SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 Jayne Culley, Peter W Nagle, John C Dawson, Neil O Carragher
Three dimensional models of cell culture enables researchers to recreate aspects of tumour biology not replicated by traditional two dimensional techniques. Here we describe a protocol to enable automated high throughput phenotypic profiling across panels of patient derived glioma stem cell spheroid models. We demonstrate the use of both live/dead cell end-points and monitor the dynamic changes in
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Reprint of: Detection and Impact of Hypoxic Regions in Multicellular Tumor Spheroid Cultures formed by Head and Neck Squamous Cell Carcinoma Cells Lines SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 David A. Close, Paul A. Johnston
In solid tumors like head and neck cancer (HNC), chronic and acute hypoxia have serious adverse clinical consequences including poorer overall patient prognosis, enhanced metastasis, increased genomic instability, and resistance to radiation-, chemo-, or immuno-therapies. However, cells in the two-dimensional monolayer cultures typically used for cancer drug discovery experience 20%-21% O2 levels (normoxic)
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Reduced levels of serum EPA and DHA identified in patients with non-small-cell lung cancer using a new rapid validated LC-MS/MS method SLAS Discov. (IF 3.1) Pub Date : 2023-12-13 Yi Wang, Tongxin Yin, Jiaoyuan Li, Xia Luo, Ke Liu, Tingting Long, Ying Shen, Liming Cheng
Background: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been suggested to play roles in various diseases, yet there is little data on their changes in patients with non-small-cell lung cancer (NSCLC). A simple LC-MS/MS method for EPA and DHA determination is critical to exploring EPA and DHA level changes in NSCLC patients. Method: 25 μL of serum was mixed with 25 μL of internal
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Virtual Plates: Getting the Best Out of High Content Screens SLAS Discov. (IF 3.1) Pub Date : 2023-11-29 Inbal Shapira Lots, Iris Alroy
High content screening (HCS) is becoming widely adopted as a high throughput screening modality, using hundred-of-thousands compounds library. The use of machine learning and artificial intelligence in image analysis is amplifying this trend. Another factor is the recognition that diverse cell phenotypes can be associated with changes in biological pathways relevant to disease processes. There are
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Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe SLAS Discov. (IF 3.1) Pub Date : 2023-11-20 Roxanne Alvarez, Jayson Kurfis, Michael Hendrickson, Daniel S. Sem
Neurological disorders associated with inflammation and oxidative stress show reduced glutathione (GSH) levels in the human brain. Drug discovery efforts and pharmacological studies would benefit from tools (e.g. chemical probes) that detect changes to oxidative stress, from the perspective of physiologically-relevant reporters like cellular thiols, including GSH. To this end, we have developed a fluorescence
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Therapeutic approaches for Type 1 Diabetes: Promising cell-based approaches to achieve ultimate success SLAS Discov. (IF 3.1) Pub Date : 2023-11-17 Sahar Sepyani, Sedigheh Momenzadeh, Saied Safabakhsh, Reza Nedaeinia, Rasoul Salehi
Type 1 Diabetes mellitus (T1DM) is a chronic metabolic disorder characterized by pancreatic β-cells destruction. Despite substantial advances in T1DM treatment, lifelong exogenous insulin administration is the mainstay of treatments, and constant control of glucose levels is still a challenge. Endogenous insulin production by replacing insulin-producing cells is an alternative, but the lack of suitable
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Screening approaches for the identification of Nrf2-Keap1 protein-protein interaction inhibitors targeting hot spot residues SLAS Discov. (IF 3.1) Pub Date : 2023-11-05 Wataru Asano, Rie Hantani, Toru Uhara, Francois Debaene, Akihiro Nomura, Keishi Yamaguchi, Tsuyoshi Adachi, Kazuki Otake, Kazuhito Harada, Yoshiji Hantani
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High-Throughput cell-based immunofluorescence assays against influenza SLAS Discov. (IF 3.1) Pub Date : 2023-11-02 Yohanka Martinez-Gzegozewska, Lynn Rasmussen, Sara McKellip, Anna Manuvakhova, N. Miranda Nebane, Andrew J. Reece, Pedro Ruiz, Melinda Sosa, Robert Bostwick, Paige Vinson
A rapid drug discovery response to influenza outbreaks with the potential to reach pandemic status could help minimize the virus's impact by reducing the time to identify anti-influenza drugs. Although several anti-influenza strategies have been considered in the search for new drugs, only a few therapeutic agents are approved for clinical use. The cytopathic effect induced by the influenza virus in
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Characterization and comparison of hypoxia inducing factors on tumor growth and metastasis between two- and three-dimensional cancer models SLAS Discov. (IF 3.1) Pub Date : 2023-10-30 Leo Li-Ying Chan, Sarah L. Kessel, Bo Lin, Anna Juncker-Jensen, Paul Weingarten
The monocarboxylic acid transporter 4 (Mct-4), a downstream biomarker of hypoxia inducing factor (HIF)-1α, is involved in the cellular response to hypoxia, as indicated by the hypoxic response element in its promoter region. Using a tumorsphere assay as an in vitro 3-dimensional (3D) model generated using 384-well ultra-low attachment (ULA) plates for cell proliferation analysis using a plate-based
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Live Cell Painting: New nontoxic dye to probe cell physiology in high content screening SLAS Discov. (IF 3.1) Pub Date : 2023-10-30 Martin Cottet, Yuniel Fernandez Marrero, Simon Mathien, Karine Audette, Raphaelle Lambert, Eric Bonneil, Kenneth Chng, Alex Campos, David W. Andrews
High-content imaging approaches, in combination with the use of perturbing agents such as small molecules or CRISPR-driven gene editing, have widely contributed to the identification of new therapeutic compounds. Thanks to recent advances in image-analysis methods, the use of high-content screens is increasingly gaining popularity and thus accelerating the discovery of new therapeutics. However, due
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Design of experiments for the automated development of a multicellular cardiac model for high-throughput screening SLAS Discov. (IF 3.1) Pub Date : 2023-10-28 Kavita Raniga, William Stebbeds, Arun Shivalingam, Michelle Pemberton, Chris Denning
Cardiovascular toxicity remains a major cause of drug attrition in early drug development, clinical trials, and post-market surveillance. In vitro assessment of cardiovascular liabilities often relies on single cell type-based model systems coupled with functional assays, like calcium flux and multielectrode arrays. Although these models offer high-throughput capabilities and demonstrate good predictivity
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Graph neural networks for the identification of novel inhibitors of a small RNA SLAS Discov. (IF 3.1) Pub Date : 2023-10-14 Christopher L. Haga, Xue D. Yang, Ibrahim S. Gheit, Donald G. Phinney
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HTS discovery of PARP1-HPF1 complex inhibitors in cancer SLAS Discov. (IF 3.1) Pub Date : 2023-10-14 Timothy Kellett, Rida Noor, Qiong Zhou, Hector Esquer, Rita Sala, Petra Stojanovic, Johannes Rudolph, Karolin Luger, Daniel V. LaBarbera
PARP1/2 inhibitors (PARPi) are effective clinically used drugs for the treatment of cancers with BRCA deficiencies. PARPi have had limited success and applicability beyond BRCA deficient cancers, and their effect is diminished by resistance mechanisms. The recent discovery of Histone PARylation Factor (HPF1) and the role it plays in the PARylation reaction by forming a shared active site with PARP1
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High-content imaging 2023: A joint special collection with the society for biomolecular imaging SLAS Discov. (IF 3.1) Pub Date : 2023-10-13 Neil O. Carragher, Judi Wardwell-Swanson, Gregory P. Way
Abstract not available
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Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors SLAS Discov. (IF 3.1) Pub Date : 2023-09-14 Edward A. FitzGerald, Darius Vagrys, Giulia Opassi, Hanna F. Klein, David J. Hamilton, Vladimir O. Talibov, Mia Abramsson, Anna Moberg, Maria T. Lindgren, Claes Holmgren, Ben Davis, Peter O'Brien, Maikel Wijtmans, Roderick E. Hubbard, Iwan J.P. de Esch, U.Helena Danielson
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Evolution and impact of high content imaging SLAS Discov. (IF 3.1) Pub Date : 2023-09-03 Gregory P. Way, Heba Sailem, Steven Shave, Richard Kasprowicz, Neil O. Carragher
The field of high content imaging has steadily evolved and expanded substantially across many industry and academic research institutions since it was first described in the early 1990′s. High content imaging refers to the automated acquisition and analysis of microscopic images from a variety of biological sample types. Integration of high content imaging microscopes with multiwell plate handling
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Nanobodies: A Game-Changer in Cell-Mediated Immunotherapy for Cancer SLAS Discov. (IF 3.1) Pub Date : 2023-08-25 Mujahed I. Mustafa, Ahmed Mohammed
Nanobodies are small, single-domain antibodies that have emerged as a promising tool in cancer immunotherapy. These molecules can target specific antigens on cancer cells and trigger an immune response against them. In this mini-review article, we highlight the potential of nanobodies in cell-mediated immunotherapy for cancer treatment. We discuss the advantages of nanobodies over conventional antibodies
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Key Aspects of Modern GPCR Drug Discovery SLAS Discov. (IF 3.1) Pub Date : 2023-08-23 Phil Addis, Utsav Bali, Frank Baron, Adrian Campbell, Steven Harborne, Liz Jagger, Gavin Milne, Martin Pearce, Elizabeth M Rosethorne, Rupert Satchell, Denise Swift, Barbara Young, John F Unitt
G-protein-coupled receptors (GPCRs) are the largest and most versatile cell surface receptor family with a broad repertoire of ligands and functions. We've learned an enormous amount about discovering drugs of this receptor class since the first GPCR was cloned and expressed in 1986, such that it's now well-recognized that GPCRs are the most successful target class for approved drugs. Here we take
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Development of assays to support identification and characterization of modulators of DExH-box helicase DHX9 SLAS Discov. (IF 3.1) Pub Date : 2023-08-23 Deepali Gotur, April Case, Julie Liu, E. Allen Sickmier, Nicholas Holt, Kevin E. Knockenhauer, Shihua Yao, Young-Tae Lee, Robert A. Copeland, Shane M. Buker, P. Ann Boriack-Sjodin
DHX9 is a DExH-box RNA helicase that utilizes hydrolysis of all four nucleotide triphosphates (NTPs) to power cycles of 3′ to 5′ directional movement to resolve and/or unwind double stranded RNA, DNA, and RNA/DNA hybrids, R-loops, triplex-DNA and G-quadraplexes. DHX9 activity is important for both viral amplification and maintaining genomic stability in cancer cells; therefore, it is a therapeutic
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Discovery of DTX3L inhibitors through a homogeneous FRET-based assay that monitors formation and removal of poly-ubiquitin chains SLAS Discov. (IF 3.1) Pub Date : 2023-08-12 Carlos Vela-Rodríguez, Ilaria Scarpulla, Yashwanth Ashok, Lari Lehtiö
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Consideration of vendor-related differences in hepatic metabolic stability data to optimize early ADME screening in drug discovery SLAS Discov. (IF 3.1) Pub Date : 2023-08-11 Pranav Shah, Elias C. Padilha, Rintaro Kato, Vishal B. Siramshetty, Wenwei Huang, Xin Xu
Hepatic metabolic stability is a crucial determinant of oral bioavailability and plasma concentrations of a compound, and its measurement is important in early drug discovery. Preliminary metabolic stability estimations are commonly performed in liver microsomal fractions. At the National Center for Advancing Translational Sciences, a single-point assay in rat liver microsomes (RLM) is employed for
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MSC.sensor: Capturing cancer cell interactions with stroma for functional profiling SLAS Discov. (IF 3.1) Pub Date : 2023-08-11 Yun Huang, Aneta Drakul, Jasmeet Sidhu, Kerstin K. Rauwolf, James Kim, Beat Bornhauser, Jean-Pierre Bourquin
Mesenchymal stromal cells (MSCs) contribute to the microenvironment regulating normal and malignant hematopoiesis, and thus may support subpopulations of cancer cells to escape therapeutic pressure. Here, we engineered bone marrow MSCs to express a synthetic CD19-sensor receptor to detect and display interacting primary CD19+ leukemia cells in coculture. This implementation provides a versatile platform
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FocA: A deep learning tool for reliable, near-real-time imaging focus analysis in automated cell assay pipelines SLAS Discov. (IF 3.1) Pub Date : 2023-08-11 Jeff Winchell, Gabriel Comolet, Geoff Buckley-Herd, Dillion Hutson, Neeloy Bose, Daniel Paull, Bianca Migliori
The increasing use of automation in cellular assays and cell culture presents significant opportunities to enhance the scale and throughput of imaging assays, but to do so, reliable data quality and consistency are critical. Realizing the full potential of automation will thus require the design of robust analysis pipelines that span the entire workflow in question. Here we present FocA, a deep learning
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Characterization of allosteric modulators that disrupt androgen receptor co-activator protein-protein interactions to alter transactivation–Drug leads for metastatic castration resistant prostate cancer SLAS Discov. (IF 3.1) Pub Date : 2023-08-06 Ashley T. Fancher, Yun Hua, David A. Close, Wei Xu, Lee A. McDermott, Christopher J. Strock, Ulises Santiago, Carlos J. Camacho, Paul A. Johnston
Three series of compounds were prioritized from a high content screening campaign that identified molecules that blocked dihydrotestosterone (DHT) induced formation of Androgen Receptor (AR) protein-protein interactions (PPIs) with the Transcriptional Intermediary Factor 2 (TIF2) coactivator and also disrupted preformed AR-TIF2 PPI complexes; the hydrobenzo-oxazepins (S1), thiadiazol-5-piperidine-carboxamides
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Automated high-throughput, high-content 3D imaging of intact pancreatic islets SLAS Discov. (IF 3.1) Pub Date : 2023-07-31 Sean M. McCarty, Martin C. Clasby, Jonathan Z. Sexton
Diabetes poses a global health crisis affecting individuals across age groups and backgrounds, with a prevalence estimate of 700 million people worldwide by 2045. Current therapeutic strategies primarily rely on insulin therapy or hypoglycemic agents, which fail to address the root cause of the disease - the loss of pancreatic insulin-producing beta-cells. Therefore, bioassays that recapitulate intact
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Role Of Vaccines Against COVID-19 Pandemic SLAS Discov. (IF 3.1) Pub Date : 2023-07-18 Professor Dr. Batool Mutar Mahdi, Dr. Mustafa Almukhtar
Coronaviruses (CoV) are one of the largest families of viruses that infect human beings causing mild common cold or severe diseases like Middle East Respiratory Syndrome (MERS-CoV), and Severe Acute Respiratory Syndrome (SARS-CoV). A new strain emerged known as novel coronavirus (nCoV) causing fatal respiratory failure disease. This virus was characterized by rapid spread from asymptomatic and symptomatic
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Assay of Sphingosine 1-phosphate Transporter Spinster Homolog 2 (Spns2) Inhibitors SLAS Discov. (IF 3.1) Pub Date : 2023-07-16 Yugesh Kharel, Tao Huang, Webster L. Santos, Kevin R. Lynch
The sphingosine-1-phosphate (S1P) pathway remains an active area of research for drug discovery because S1P modulators are effective medicine for autoimmune diseases such as multiple sclerosis and ulcerative colitis. As such, other nodes in the pathway can be probed for alternative therapeutic candidates. As S1P elicits its function in an ‘outside-in’ fashion, targeting the transporter, Spns2, which
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Identification of tau-tubulin kinase 1 inhibitors by microfluidics-based mobility shift assay from a kinase inhibitor library SLAS Discov. (IF 3.1) Pub Date : 2023-07-01 Jinlei Wang, Ying Lin, Xiaoyu Xu, Yonghui Wang, Qiong Xie
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Novel beta-glucocerebrosidase chaperone compounds identified from cell-based screening reduce pathologically accumulated glucosylsphingosine in iPS-derived neuronal cells SLAS Discov. (IF 3.1) Pub Date : 2023-06-25 Yusuke Naito, Sou Sakamoto, Takuto Kojima, Misaki Homma, Maiko Tanaka, Hideki Matsui
The beta-glucocerebrosidase (GBA1) gene encodes the lysosomal beta-glucocerebrosidase (GCase) that metabolizes the lipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Biallelic loss-of-function mutations in GBA1 such as L444P cause Gaucher disease (GD), which is the most prevalent lysosomal storage disease and is histopathologically characterized by abnormal accumulation of the GCase
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HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin SLAS Discov. (IF 3.1) Pub Date : 2023-06-10 JM Muretta, D Rajasekaran, Y Blat, S Little, M Myers, C Nair, B Burdekin, SL Yuen, N Jimenez, P Guhathakurta, A Wilson, AR Thompson, N Surti, D Connors, P Chase, D Harden, CM Barbieri, L Adam, DD Thomas
Small molecules that bind to allosteric sites on target proteins to alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays are needed to facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection of fluorescence resonance energy transfer (FRET), which enables
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Emerging drug discovery ecosystems SLAS Discov. (IF 3.1) Pub Date : 2023-05-31 Elizabeth R. Sharlow
Abstract not available
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Development of an enzyme-coupled activity assay for Janus kinase 2 inhibitor screening SLAS Discov. (IF 3.1) Pub Date : 2023-05-05 Angelika Pölläniemi, Anniina Virtanen, Olli Silvennoinen, Teemu Haikarainen
JAK2 transmits signals of several important cytokines, such as growth hormone and erythropoietin. The interest toward the therapeutic targeting of JAK2 was boosted in 2005, when the somatic JAK2 V617F mutation, responsible for the majority of myeloproliferative neoplasms (MPNs) was discovered. JAK2 inhibitors have been approved for MPN therapy and they are effective in alleviating symptoms and improving
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High-throughput approaches to uncover synergistic drug combinations in leukemia SLAS Discov. (IF 3.1) Pub Date : 2023-04-29 Emma J. Chory, Meng Wang, Michele Ceribelli, Aleksandra M Michalowska, Stefan Golas, Erin Beck, Carleen Klumpp-Thomas, Lu Chen, Crystal McKnight, Zina Itkin, Kelli M. Wilson, David Holland, Sanjay Divakaran, James Bradner, Javed Khan, Berkley E. Gryder, Craig J. Thomas, Benjamin Z. Stanton
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Development of a high-throughput TR-FRET screening assay for LAG-3/FGL1 interaction SLAS Discov. (IF 3.1) Pub Date : 2023-04-28 Somaya A. Abdel-Rahman, Longfei Zhang, Moustafa T. Gabr
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Application of human iPSC-derived macrophages in a miniaturized high-content-imaging-based efferocytosis assay SLAS Discov. (IF 3.1) Pub Date : 2023-04-16 Sarah Bitzer, Mozhgan Dehghan Harati, Karim C. El Kasmi, Daniela Schloesser, Julia Sauer, Heiko Olbrich, Michael Schuler, Florian Gantner, Ralf Heilker
Macrophages play a pivotal role in drug discovery due to their key regulatory functions in health and disease. Overcoming the limited availability and donor variability of human monocyte-derived macrophages (MDMs), human induced pluripotent stem cell (iPSC)-derived macrophages (IDMs) could provide a promising tool for both disease modeling and drug discovery. To access large numbers of model cells
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Label-free high-throughput screening via acoustic ejection mass spectrometry put into practice SLAS Discov. (IF 3.1) Pub Date : 2023-04-08 Martin Winter, Roman P. Simon, Tim T. Häbe, Robert Ries, Yuting Wang, David Kvaskoff, Amaury Fernández-Montalván, Andreas H. Luippold, Frank H. Büttner, Wolfgang Reindl
Acoustic droplet ejection-open port interface-mass spectrometry (ADE-OPI-MS) is a novel label-free analytical technique, promising to become a versatile readout for high-throughput screening (HTS) applications. The recent introduction of ADE-OPI-MS devices to the laboratory equipment market, paired with their compatibility with laboratory automation platforms, should facilitate the adoption of this
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Fluorescent probe for the identification of potent inhibitors of the macrophage infectivity potentiator (Mip) protein of Burkholderia pseudomallei SLAS Discov. (IF 3.1) Pub Date : 2023-03-29 Nicolas Julian Scheuplein, Theresa Lohr, Mirella Vivoli Vega, Dyan Ankrett, Florian Seufert, Lukas Kirchner, Nicholas J. Harmer, Ulrike Holzgrabe
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In Vitro three-dimensional (3D) cell culture tools for spheroid and organoid models SLAS Discov. (IF 3.1) Pub Date : 2023-03-28 Sang-Yun Lee, In-Seong Koo, Hyun Ju Hwang, Dong Woo Lee
Three-dimensional (3D) cell culture technology has been steadily studied since the 1990′s due to its superior biocompatibility compared to the conventional two-dimensional (2D) cell culture technology, and has recently developed into an organoid culture technology that further improved biocompatibility. Since the 3D culture of human cell lines in artificial scaffolds was demonstrated in the early 90′s
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Evaluating the affinity and kinetics of small molecule glycomimetics for human and mouse galectin-3 using surface plasmon resonance SLAS Discov. (IF 3.1) Pub Date : 2023-03-28 Henry Kim, Nathalie Weidner, Céline Ronin, Emmanuel Klein, James A. Roper, Barbro Kahl-Knutson, Kristoffer Peterson, Hakon Leffler, Ulf J. Nilsson, Anders Pedersen, Fredrik R. Zetterberg, Robert J. Slack
Galectin-3 is a beta-galactoside-binding mammalian lectin that is one of a 15-member galectin family that can bind several cell surface glycoproteins via its carbohydrate recognition domain (CRD). As a result, it can influence a range of cellular processes including cell activation, adhesion and apoptosis. Galectin-3 has been implicated in various diseases, including fibrotic disorders and cancer,
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Comparison of two supporting matrices for patient-derived cancer cells in 3D drug sensitivity and resistance testing assay (3D-DSRT) SLAS Discov. (IF 3.1) Pub Date : 2023-03-20 Michaela Feodoroff, Piia Mikkonen, Laura Turunen, Antti Hassinen, Lauri Paasonen, Lassi Paavolainen, Swapnil Potdar, Astrid Murumägi, Olli Kallioniemi, Vilja Pietiäinen
Central to the success of functional precision medicine of solid tumors is to perform drug testing of patient-derived cancer cells (PDCs) in tumor-mimicking ex vivo conditions. While high throughput (HT) drug screening methods have been well-established for cells cultured in two-dimensional (2D) format, this approach may have limited value in predicting clinical responses. Here, we describe the results
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A novel fluorogenic reporter substrate for 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 (PLCγ2): Application to high-throughput screening for activators to treat Alzheimer's disease SLAS Discov. (IF 3.1) Pub Date : 2023-03-17 Ramya Visvanathan, Tadanobu Utsuki, Daniel E. Beck, Emma Lendy, Kuai-lin Sun, Yinghui Liu, Kirk W. Hering, Andrew Mesecar, Zhong-Yin Zhang, Karson S. Putt
A rare coding variant in PLCγ2 (P522R) expressed in microglia induces a mild activation of enzymatic activity when compared to wild-type. This mutation is reported to be protective against the cognitive decline associated with late-onset Alzheimer's disease (LOAD) and therefore, activation of wild-type PLCγ2 has been suggested as a potential therapeutic target for the prevention and treatment of LOAD
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Drug discovery efforts at George Mason University SLAS Discov. (IF 3.1) Pub Date : 2023-03-14 Ali Andalibi, Remi Veneziano, Mikell Paige, Michael Buschmann, Amanda Haymond, Virginia Espina, Alessandra Luchini, Lance Liotta, Barney Bishop, Monique Van Hoek
With over 39,000 students, and research expenditures in excess of $200 million, George Mason University (GMU) is the largest R1 (Carnegie Classification of very high research activity) university in Virginia. Mason scientists have been involved in the discovery and development of novel diagnostics and therapeutics in areas as diverse as infectious diseases and cancer. Below are highlights of the efforts
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Merging cultures and disciplines to create a drug discovery ecosystem at Virginia commonwealth university: Medicinal chemistry, structural biology, molecular and behavioral pharmacology and computational chemistry SLAS Discov. (IF 3.1) Pub Date : 2023-02-28 Glen E. Kellogg, Yana Cen, Malgorzata Dukat, Keith C. Ellis, Youzhong Guo, Jiong Li, Aaron E. May, Martin K. Safo, Shijun Zhang, Yan Zhang, Umesh R. Desai
The Department of Medicinal Chemistry, together with the Institute for Structural Biology, Drug Discovery and Development, at Virginia Commonwealth University (VCU) has evolved, organically with quite a bit of bootstrapping, into a unique drug discovery ecosystem in response to the environment and culture of the university and the wider research enterprise. Each faculty member that joined the department