SLAS Discovery最新文献

{"title":"Open-source electrophilic fragment screening platform to identify chemical starting points for UCHL1 covalent inhibitors","authors":"Scott B. Ficarro ,&nbsp;Zachary H. Marto ,&nbsp;Nicholas M. Girardi ,&nbsp;Dingyu Deng ,&nbsp;Isabella Jaen Maisonet ,&nbsp;Guillaume Adelmant ,&nbsp;Laura E. Fleming ,&nbsp;Mona Sharafi ,&nbsp;Isidoro Tavares ,&nbsp;Andrew Zhao ,&nbsp;HyoJeon Kim ,&nbsp;Hyuk-Soo Seo ,&nbsp;Sirano Dhe-Paganon ,&nbsp;Sara J. Buhrlage ,&nbsp;Jarrod A. Marto","doi":"10.1016/j.slasd.2024.100198","DOIUrl":"10.1016/j.slasd.2024.100198","url":null,"abstract":"<div><div>Target-based screening of covalent fragment libraries with mass spectrometry has emerged as a powerful strategy to identify chemical starting points for small molecule inhibitors or find new binding pockets on proteins of interest. These libraries span diverse chemical space with a modest number of compounds. Screening covalent fragments against purified protein targets reduces the demands on the mass spectrometer with respect to absolute throughput, detection limit, and dynamic range. Given these relaxed analytical requirements, we sought to develop an open-source, medium-throughput mass spectrometry system for target-based covalent fragment screening. Our platform comprises automated, dual LC desalting columns integrated with electrospray ionization for rapid sample introduction and mass spectrometry detection. The system is operated through a simple Python graphical user interface running on commodity microcontroller boards which allow integration with diverse liquid chromatography and mass spectrometry instruments. We provide scripts for fragment pooling, construction of sample batches, along with routines for data processing and visualization. The system enables primary screening of ∼10,000 covalent fragments per day in pooled format. In a proof-of-concept study we executed primary and secondary screens to identify 27 hit fragments against UCHL1, a deubiquitinating enzyme that is emerging as a drug target of interest across multiple clinical indications. We validated and triaged these covalent compounds through a series of orthogonal biochemical and chemoproteomic assays. The most promising chloroacetamide covalent fragment inhibited UCHL1 activity in vitro (IC₅₀ &lt; 5 µM) and exhibited dose-dependent binding along with good selectivity against 57 cellular DUBs as quantified by activity-based protein profiling.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 8","pages":"Article 100198"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142775432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Varieties of interactions of anti-CD133 aptamers with cell cultures from patient glioblastoma","authors":"Olga Antipova ,&nbsp;Valeria Moiseenko ,&nbsp;Fatima Dzarieva ,&nbsp;Ekaterina Savchenko ,&nbsp;Igor Pronin ,&nbsp;Galina Pavlova ,&nbsp;Alexey Kopylov","doi":"10.1016/j.slasd.2024.100195","DOIUrl":"10.1016/j.slasd.2024.100195","url":null,"abstract":"<div><div>Development of aptatheranostics for glioblastoma (GB) requires investigating aptamer interactions with cells. The paper has described flow cytometry (FC) assessment of direct interactions of fluorescent anti-CD133 aptamers with cells, focusing on cell cultures derived from patient GB (CCPGB). Conventional cell lines with different levels of CD133 mRNA, Caco-2 and HCT116, were used to compare interactions with known 2′FY-RNA aptamer A15 and DNA aptamers of Ap and Cs series, labeled with FAM and Cy5. In addition, interactions of certain non-aptameric oligonucleotides were studied. In the case of antibody interactions with cells, FC signals, mean fluorescence intensities (MFIs), correlated with sizable amounts of CD133 mRNA in Caco-2 cells, and CCPGBs 107 and G01. Unexpectedly, MFI <em>per se</em> could not be the solid indicator of specific interactions of aptamer - CD133/cell. Instead, two types of interactions, target CD133-driven and off-target membrane-associated ones, contribute to MFI. The latter was notably observed for CCPGB Sus/fP2 with tiny CD133 mRNA amount. To prove specificity of aptamer - CD133/cell interactions, titration experiments have been performed, revealing half-saturation concentrations of 120±27 for 2′FY-RNA A15 and 180±12 for DNA Cs5 with Caco-2 cells. This knowledge is an essential step to develop aptatheranostics for GB.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 8","pages":"Article 100195"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β receptor-specific NanoBRET Target Engagement in living cells for high-throughput kinase inhibitor screens","authors":"Marius Wits ,&nbsp;Nicole Haarmans ,&nbsp;Gonzalo Sanchez-Duffhues ,&nbsp;Marie-José Goumans","doi":"10.1016/j.slasd.2024.100196","DOIUrl":"10.1016/j.slasd.2024.100196","url":null,"abstract":"<div><div>Targeting transforming growth factor-β (TGF-β) receptors is a promising pharmacological approach to normalize aberrant signaling in genetic and non-genetic TGF-β associated diseases including fibrosis, cancer, cardiovascular and musculoskeletal disorders. To identify novel TGF-β receptor kinase inhibitors, methods like in vitro kinase assays, western blot or transcriptional reporter assays are often used for screening purposes. While these methods may have certain advantages, the lack of integration of key features such as receptor specificity, high-throughput capability, and cellular context resemblance remains a major disadvantage. This deficiency could ultimately hinder the translation of study outcomes into later (clinical) stages of drug development. In this study, we introduce an adjusted and optimized live cell NanoBRET Target Engagement (TE)-based method to identify TGF-β receptor specific kinase inhibitors. This comprehensive toolkit contains various TGF-β type I and type II receptors, with corresponding nanoBRET tracers, and disease-related cell lines, including novel non-commercially available materials. The nanoBRET capacity and kinase inhibitory window can be significantly enhanced for functional measurements when stable expression cell lines and substantially low tracer concentrations are used. In addition, this system can be tailored to study TGF-β associated genetic disorders and possibly be used to screen for disease-specific therapeutics. Therefore, the use of this optimized, live cell, antibody-independent nanoBRET Target Engagement assay is highly encouraged for future high-throughput compound screens targeting TGF-β/BMP receptors.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 8","pages":"Article 100196"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High throughput application of the NanoBiT Biochemical Assay for the discovery of selective inhibitors of the interaction of PI3K-p110α with KRAS","authors":"Mohamed Ismail ,&nbsp;Gareth Davies ,&nbsp;Graham Sproat ,&nbsp;Tiziana Monteverde ,&nbsp;Jonathan Tart ,&nbsp;Marta Acebrón-García-de-Eulate ,&nbsp;Andrea Gohlke ,&nbsp;David Hancock ,&nbsp;Santosh Adhikari ,&nbsp;Sandra Stefanovic-Barrett ,&nbsp;David M Smith ,&nbsp;Vikki Flemington ,&nbsp;Emma S. Gleave-Hanford ,&nbsp;Geoffrey A. Holdgate ,&nbsp;Jason G. Kettle ,&nbsp;Julian Downward","doi":"10.1016/j.slasd.2024.100197","DOIUrl":"10.1016/j.slasd.2024.100197","url":null,"abstract":"<div><div>The NanoBiT Biochemical Assay (NBBA) was designed as a biochemical format of the NanoBiT cellular assay, aiming to screen weak protein-protein interactions (PPIs) in mammalian cell lysates. Here we present a High Throughput Screening (HTS) application of the NBBA to screen small molecule and fragment libraries to identify compounds that block the interaction of KRAS-G12D with phosphatidylinositol 3-kinase (PI3K) p110α. This interaction promotes PI3K activity, resulting in the promotion of cell growth, proliferation and survival, and is required for tumour initiation and growth in mouse lung cancer models, whilst having little effect on the health of normal adult mice, establishing the significance of the p110α/KRAS interaction as an oncology drug target. Despite the weak binding affinity of the p110α/KRAS interaction (K_D = 3 μM), the NBBA proved to be robust and displayed excellent Z’-factor statistics during the HTS primary screening of 726,000 compounds, which led to the identification of 8,000 active compounds. A concentration response screen comparing KRAS/p110α with two closely related PI3K isoforms, p110δ and p110γ, identified selective p110α-specific compounds and enabled derivation of an IC₅₀ for these hits. We identified around 30 compounds showing greater than 20-fold selectivity towards p110α versus p110δ and p110γ with IC₅₀ &lt; 2 μM. By using Differential Scanning Fluorimetry (DSF) we confirmed several compounds that bind directly to purified p110α. The most potent hits will be followed up by co-crystallization with p110α to aid further elucidation of the nature of the interaction and extended optimisation of these compounds.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 8","pages":"Article 100197"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Standards for reporting optical biosensor experiments (STROBE): Improving standards in the reporting of optical biosensor-based data in the literature","authors":"Paul E. Belcher ,&nbsp;Anna Moberg ,&nbsp;Michael B. Murphy","doi":"10.1016/j.slasd.2024.100192","DOIUrl":"10.1016/j.slasd.2024.100192","url":null,"abstract":"<div><div>The number of peer-reviewed publications that feature biosensor data increases every year. A search of PubMed using common technique terminology, including bio-layer interferometry (BLI), surface plasmon resonance (SPR) and grating-coupled interferometry (GCI) generated more than 2500 scientific papers from 2022. Compared to 2009, when David Myszka and Rebecca Rich presented their most recent review of biosensor literature (Rich and Myszka, 2011), this number has nearly doubled. With this increasing number of publications comes an increasing need for standardization of the way biosensor data is reported in journals to allow for replication of the experiments that were performed. Biosensor data is often poorly described in papers which makes it difficult, if not impossible, to replicate the experiment. Critical information typically missing includes sample preparation, method settings, and data evaluation details. We have also found published work in which the authors have failed to report the type of sensor that was used, or which biosensor instrumentation was used. To come to terms with this growing problem, we propose a standardization of the way biosensor data is reported in scientific journals. We call this standard STROBE, standards for reporting optical biosensor experiments.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 8","pages":"Article 100192"},"PeriodicalIF":2.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mechanism of action-reflective, dual cell-based bioassay for determining the bioactivity of sclerostin-neutralizing antibodies","authors":"Suzhen Wei ,&nbsp;Qiang Wu ,&nbsp;Chunlai Cao ,&nbsp;Zhuoni Yang ,&nbsp;Jianrui Shi ,&nbsp;Jingqun Huang ,&nbsp;Hua He ,&nbsp;Yongjie Lai ,&nbsp;Jing Li","doi":"10.1016/j.slasd.2024.100187","DOIUrl":"10.1016/j.slasd.2024.100187","url":null,"abstract":"<div><div>Osteoporosis is a major threat to the elderly worldwide. The Wnt signaling pathway plays a critical role in bone development and homeostasis. Sclerostin, a Wnt ligand inhibitor, competes with Wnt ligands for low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) on osteoblasts, thereby suppressing bone formation. Sclerostin-neutralizing monoclonal antibodies (mAbs) have emerged as a potential bone-forming therapy for osteoporosis. A cell-based bioassay which determines the relative activity of a product, related to its mechanism of action, is of great importance from drug discovery to quality control and batch release. Currently used cell-based bioassays for sclerostin-neutralizing mAbs usually use Wnt1 or Wnt3a to stimulate the Wnt pathway; sclerostin is a direct inhibitor of Wnt1 but not Wnt3a. Wnt1 is a highly hydrophobic protein that binds to the producing cell membrane and acts in a juxtacrine manner to stimulate the Wnt pathway in neighboring cells. Bioassays for drugs that induce Wnt1 signaling should be performed in a juxtacrine manner. Here, we present a mechanism of action-reflective, dual cell-based reporter gene assay. In this assay, Wnt1 producer cells are co-cultured with cells containing the Wnt reporter genes, Wnt1 on the producer cells activates the Wnt signaling pathway in the reporter cells that are in direct cell-to-cell contact, and sclerostin-neutralizing mAbs specifically and effectively antagonize the sclerostin-mediated Wnt reporter gene suppression. This bioassay demonstrates good specificity, accuracy, linearity, and precision and is suitable for quality control, stability testing, batch release, and biosimilarity assessment of sclerostin-neutralizing mAbs.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 7","pages":"Article 100187"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recapitulation of NOD/RIPK2 signaling in iPSC-derived macrophages","authors":"Mozhgan Dehghan Harati ,&nbsp;Jim King ,&nbsp;Simon Langer ,&nbsp;Florian Binder ,&nbsp;Ralf Heilker","doi":"10.1016/j.slasd.2024.100185","DOIUrl":"10.1016/j.slasd.2024.100185","url":null,"abstract":"<div><div>Human induced pluripotent stem cell (iPSC)-derived macrophages (IDMs) present a valuable substitute for monocyte-derived macrophages (MDMs) in order to study inflammation pathways in vitro. Through optimization of an IDM differentiation protocol, a six-fold increase in the production yield of myeloid progenitors was achieved. The derived IDMs were further characterized with respect to nucleotide-binding oligomerization domain (NOD) and receptor-interacting serine/threonine-protein kinase 2 (RIPK2) signaling, a key regulatory pathway for autoimmune diseases. The IDM cells recapitulated MDM biology with respect to the proinflammatory chemokine and inflammatory cytokine fingerprint more closely than THP-1 cells. When assessing RIPK2 modulation effect on tumor necrosis factor α (TNF-α), a cardinal mediator of inflammation, a similar pharmacological effect of RIPK2 inhibitors was observed in IDMs and MDMs. Additionally, IDMs and MDMs displayed a similar transcription and pathway profile in response to NOD1/2 stimulation and pharmacological inhibition of RIPK2. In summary, the enhanced myeloid production yield in the improved IDM differentiation protocol offers new opportunities for utilizing physiologically relevant macrophage models in the context of inflammatory diseases.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 7","pages":"Article 100185"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor","authors":"Thomas S. Dexheimer ,&nbsp;Nathan P. Coussens ,&nbsp;Thomas Silvers ,&nbsp;Eric M. Jones ,&nbsp;Li Chen ,&nbsp;Jianwen Fang ,&nbsp;Joel Morris ,&nbsp;Jeffrey A. Moscow ,&nbsp;James H. Doroshow ,&nbsp;Beverly A. Teicher","doi":"10.1016/j.slasd.2024.100186","DOIUrl":"10.1016/j.slasd.2024.100186","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes of drug transporters and metabolic enzymes to detoxify small molecule xenobiotics. It has a complex role in cancer biology, influencing both the progression and suppression of tumors by modulating malignant properties of tumor cells and anti-tumor immunity, depending on the specific tumor type and developmental stage. This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials. To identify small molecule anticancer agents that might be combined with AhR antagonists for cancer therapy, a high-throughput combination screen was performed using multi-cell type tumor spheroids grown from malignant cells, endothelial cells, and mesenchymal stem cells. The AhR selective antagonists BAY 2416964, GNF351, and CH-223191 were tested individually and in combination with twenty-five small molecule anticancer agents. As single agents, BAY 2416964 and CH-223191 showed minimal activity, whereas GNF351 reduced the viability of some spheroid models at concentrations greater than 1 µM. The activity of most combinations aligned well with the single agent activity of the combined agent, without apparent contributions from the AhR antagonist. All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor. These combinations were active in spheroids containing bladder, breast, ovary, kidney, pancreas, colon, and lung tumor cell lines. The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 7","pages":"Article 100186"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design considerations when creating a high throughput screen-compatible in vitro model of osteogenesis","authors":"Stephanie E. Doyle,&nbsp;Courtney N. Cazzola,&nbsp;Cynthia M. Coleman","doi":"10.1016/j.slasd.2024.100184","DOIUrl":"10.1016/j.slasd.2024.100184","url":null,"abstract":"<div><div>Inducing osteogenic differentiation <em>in vitro</em> is useful for the identification and development of bone regeneration therapies as well as modelling bone disorders. To couple <em>in vitro</em> models with high throughput screening techniques retains the assay's relevance in research while increasing its therapeutic impact. Miniaturizing, automating and/or digitalizing <em>in vitro</em> assays will reduce the required quantity of cells, biologic stimulants, culture/output assay reagents, time and cost. This review highlights the design and workflow considerations for creating a high throughput screen-compatible model of osteogenesis, comparing and contrasting osteogenic cell type, assay fabrication and culture methodology, osteogenic induction approach and repurposing existing output techniques.</div></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 7","pages":"Article 100184"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an automated 3D high content cell screening platform for organoid phenotyping","authors":"Suleyman B. Bozal ,&nbsp;Greg Sjogren ,&nbsp;Antonio P. Costa ,&nbsp;Joseph S. Brown ,&nbsp;Shannon Roberts ,&nbsp;Dylan Baker ,&nbsp;Paul Gabriel Jr. ,&nbsp;Benjamin T. Ristau ,&nbsp;Michael Samuels ,&nbsp;William F. Flynn ,&nbsp;Paul Robson ,&nbsp;Elise T. Courtois","doi":"10.1016/j.slasd.2024.100182","DOIUrl":"10.1016/j.slasd.2024.100182","url":null,"abstract":"<div><p>The use of organoid models in biomedical research has grown substantially since their inception. As they gain popularity among scientists seeking more complex and biologically relevant systems, there is a direct need to expand and clarify potential uses of such systems in diverse experimental contexts. Herein we outline a high-content screening (HCS) platform that allows researchers to screen drugs or other compounds against three-dimensional (3D) cell culture systems in a multi-well format (384-well). Furthermore, we compare the quality of robotic liquid handling with manual pipetting and characterize and contrast the phenotypic effects detected by confocal imaging and biochemical assays in response to drug treatment. We show that robotic liquid handling is more consistent and amendable to high throughput experimental designs when compared to manual pipetting due to improved precision and automated randomization capabilities. We also show that image-based techniques are more sensitive to detecting phenotypic changes within organoid cultures than traditional biochemical assays that evaluate cell viability, supporting their integration into organoid screening workflows. Finally, we highlight the enhanced capabilities of confocal imaging in this organoid screening platform as they relate to discerning organoid drug responses in single-well co-cultures of organoids derived from primary human biopsies and patient-derived xenograft (PDX) models. Altogether, this platform enables automated, imaging-based HCS of 3D cellular models in a non-destructive manner, opening the path to complementary analysis through integrated downstream methods.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":"29 7","pages":"Article 100182"},"PeriodicalIF":2.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555224000443/pdfft?md5=95bb4a25e3d1035eb2e9758c7aafa3a7&pid=1-s2.0-S2472555224000443-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}