SLAS Discovery最新文献

{"title":"Multiplexed experimental strategies for fragment library screening against challenging drug targets using SPR biosensors","authors":"Edward A. FitzGerald ,&nbsp;Darius Vagrys ,&nbsp;Giulia Opassi ,&nbsp;Hanna F. Klein ,&nbsp;David J. Hamilton ,&nbsp;Vladimir O. Talibov ,&nbsp;Mia Abramsson ,&nbsp;Anna Moberg ,&nbsp;Maria T. Lindgren ,&nbsp;Claes Holmgren ,&nbsp;Ben Davis ,&nbsp;Peter O'Brien ,&nbsp;Maikel Wijtmans ,&nbsp;Roderick E. Hubbard ,&nbsp;Iwan J.P. de Esch ,&nbsp;U.Helena Danielson","doi":"10.1016/j.slasd.2023.09.001","DOIUrl":"10.1016/j.slasd.2023.09.001","url":null,"abstract":"<div><p>Surface plasmon resonance (SPR) biosensor methods are ideally suited for fragment-based lead discovery.  However, generally applicable experimental procedures and detailed protocols are lacking, especially for structurally or physico-chemically challenging targets or when tool compounds are not available. Success depends on accounting for the features of both the target and the chemical library, purposely designing screening experiments for identification and validation of hits with desired specificity and mode-of-action, and availability of orthogonal methods capable of confirming fragment hits. The range of targets and libraries amenable to an SPR biosensor-based approach for identifying hits is considerably expanded by adopting multiplexed strategies, using multiple complementary surfaces or experimental conditions. Here we illustrate principles and multiplexed approaches for using flow-based SPR biosensor systems for screening fragment libraries of different sizes (90 and 1056 compounds) against a selection of challenging targets. It shows strategies for the identification of fragments interacting with 1) large and structurally dynamic targets, represented by acetyl choline binding protein (AChBP), a Cys-loop receptor ligand gated ion channel homologue, 2) targets in multi protein complexes, represented by lysine demethylase 1 and a corepressor (LSD1/CoREST), 3) structurally variable or unstable targets, represented by farnesyl pyrophosphate synthase (FPPS), 4) targets containing intrinsically disordered regions, represented by protein tyrosine phosphatase 1B  (PTP1B), and 5) aggregation-prone proteins, represented by an engineered form of human tau  (tau K18^M). Practical considerations and procedures accounting for the characteristics of the proteins and libraries, and that increase robustness, sensitivity, throughput and versatility are highlighted. The study shows that the challenges for addressing these types of targets is not identification of potentially useful fragments per se, but establishing methods for their validation and evolution into leads.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000679/pdfft?md5=e9a7100ac306d5de9cdd29e39a98f3eb&pid=1-s2.0-S2472555223000679-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10253726","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":"Key aspects of modern GPCR drug discovery","authors":"Phil Addis ,&nbsp;Utsav Bali ,&nbsp;Frank Baron ,&nbsp;Adrian Campbell ,&nbsp;Steven Harborne ,&nbsp;Liz Jagger ,&nbsp;Gavin Milne ,&nbsp;Martin Pearce ,&nbsp;Elizabeth M Rosethorne ,&nbsp;Rupert Satchell ,&nbsp;Denise Swift ,&nbsp;Barbara Young ,&nbsp;John F Unitt","doi":"10.1016/j.slasd.2023.08.007","DOIUrl":"10.1016/j.slasd.2023.08.007","url":null,"abstract":"<div><p>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 the reader through a GPCR drug discovery journey from target to the clinic, highlighting the key learnings, best practices, challenges, trends and insights on discovering drugs that ultimately modulate GPCR function therapeutically in patients. The future of GPCR drug discovery is inspiring, with more desirable drug mechanisms and new technologies enabling the delivery of better and more successful drugs.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000643/pdfft?md5=e5ba61e29a8a7d8a39b708740744ab68&pid=1-s2.0-S2472555223000643-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10074621","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":"Consideration of vendor-related differences in hepatic metabolic stability data to optimize early ADME screening in drug discovery","authors":"Pranav Shah ,&nbsp;Elias C. Padilha ,&nbsp;Rintaro Kato ,&nbsp;Vishal B. Siramshetty ,&nbsp;Wenwei Huang ,&nbsp;Xin Xu","doi":"10.1016/j.slasd.2023.08.002","DOIUrl":"10.1016/j.slasd.2023.08.002","url":null,"abstract":"<div><p>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 initial stability assessment (Tier I) and a multi-point detailed stability assay is employed as a Tier II assay for promising compounds. Although the <em>in vitro</em> and <em>in vivo</em> metabolic stability of compounds typically exhibit good correlation, conflicting results may arise in certain cases. While investigating one such instance, we serendipitously found vendor-related RLM differences in metabolic stability and metabolite formation, which had implications for <em>in vitro</em> and <em>in vivo</em> correlations. In this study, we highlight the importance of considering vendor differences in hepatic metabolic stability data and discuss strategies to avoid these pitfalls.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S247255522300059X/pdfft?md5=97f05a382d32c16ef121ece3e85f6f38&pid=1-s2.0-S247255522300059X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10064905","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 cell-based immunofluorescence assays against influenza","authors":"Yohanka Martinez-Gzegozewska,&nbsp;Lynn Rasmussen,&nbsp;Sara McKellip,&nbsp;Anna Manuvakhova,&nbsp;N. Miranda Nebane,&nbsp;Andrew J. Reece,&nbsp;Pedro Ruiz,&nbsp;Melinda Sosa,&nbsp;Robert Bostwick,&nbsp;Paige Vinson","doi":"10.1016/j.slasd.2023.10.008","DOIUrl":"10.1016/j.slasd.2023.10.008","url":null,"abstract":"<div><p>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 Madin Darby canine kidney (MDCK) cells has been widely used for high-throughput anti-influenza drug screening, but the fact that the MDCK cells are not human cells constitutes a disadvantage when searching for new therapeutic agents for human use. We have developed a highly sensitive cell-based imaging assay for the identification of inhibitors of influenza A and B virus that is high-throughput compatible using the A549 human cell line. The assay has also been optimized for the assessment of the neutralizing effect of anti-influenza antibodies in the absence of trypsin, which allows testing of purified antibodies and serum samples. This assay platform can be applied to full high-throughput screening campaigns or later stages requiring quantitative potency determinations for structure-activity relationships.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000783/pdfft?md5=fb5946572ad6363ceeb2a134add0ee25&pid=1-s2.0-S2472555223000783-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71489818","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":"Virtual plates: Getting the best out of high content screens","authors":"Inbal Shapira Lots,&nbsp;Iris Alroy","doi":"10.1016/j.slasd.2023.11.004","DOIUrl":"10.1016/j.slasd.2023.11.004","url":null,"abstract":"<div><p>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 numerous challenges in HCS campaigns. These include limited ability to support replicates, low availability of precious and unique cells or reagents, high number of experimental batches, lengthy preparation of cells for imaging, image acquisition time (45–60 min per plate) and image processing time, deterioration of image quality with time post cell fixation and variability within wells and batches. To take advantage of the data in HCS, cell population based rather than well-based analyses are required. Historically, statistical analysis and hypothesis testing played only a limited role in non-high content high throughput campaigns. Thus, only a limited number of standard statistical criteria for hit selection in HCS have been developed so far. In addition to complex biological content in HCS campaigns, additional variability is impacted by cell and reagent handling and by instruments which may malfunction or perform unevenly. Together these can cause a significant number of wells or plates to fail. Here we describe an automated approach for hit analysis and detection in HCS. Our approach automates HCS hit detection using a methodology that is based on a documented statistical framework. We introduce the <em>Virtual Plate</em> concept in which selected wells from different plates are collated into a new, virtual plate. This allows the rescue and analysis of compound wells which have failed due to technical issues as well as to collect hit wells into one plate, allowing the user easier access to the hit data.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000825/pdfft?md5=d5cdda9df9597ebac39e264c5b0778d3&pid=1-s2.0-S2472555223000825-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138464893","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":"Genome-scale functional genomics screening highlights genes impacting protein fucosylation in Chinese hamster ovary cells","authors":"Kari Barlan ,&nbsp;Gaurang P Bhide ,&nbsp;Derek R White ,&nbsp;Marc R Lake ,&nbsp;Charles Lu ,&nbsp;Stephanie E Rieder ,&nbsp;Lianchun Fan ,&nbsp;Chen-Lin Hsieh","doi":"10.1016/j.slasd.2023.10.004","DOIUrl":"10.1016/j.slasd.2023.10.004","url":null,"abstract":"<div><p>N-linked glycosylation is a common post-translational modification that has various effects on multiple types of proteins. The extent to which an N-linked glycoprotein is modified and the identity of glycans species involved is of great interest to the biopharmaceutical industry, since glycosylation can impact the efficacy and safety of therapeutic monoclonal antibodies (mAbs). mAbs lacking core fucose, for example, display enhanced clinical efficacy through increased antibody-dependent cellular cytotoxicity. We performed a genome-wide CRISPR knockout screen in Chinese hamster ovary (CHO) cells, the workhorse cell culture system for industrial production of mAbs, aimed at identifying novel regulators of protein fucosylation. Using a lectin binding assay, we identified 224 gene perturbations that significantly alter protein fucosylation, including well-known glycosylation genes. This functional genomics framework could readily be extended and applied to study the genetic pathways involved in regulation of other glycoforms. We hope this resource will provide useful guidance toward the development of next generation CHO cell lines and mAb therapeutics.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000709/pdfft?md5=fdab2df9e45966a2ceb42de024e1fc83&pid=1-s2.0-S2472555223000709-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41241998","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":"Therapeutic approaches for Type 1 Diabetes: Promising cell-based approaches to achieve ultimate success","authors":"Sahar Sepyani ,&nbsp;Sedigheh Momenzadeh ,&nbsp;Saied Safabakhsh ,&nbsp;Reza Nedaeinia ,&nbsp;Rasoul Salehi","doi":"10.1016/j.slasd.2023.11.002","DOIUrl":"10.1016/j.slasd.2023.11.002","url":null,"abstract":"<div><p>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 donors is accounted as one of the main obstacles to its widespread application.</p><p>The research and trials overview demonstrates that endogenous production of insulin has started to go beyond the deceased-derived to stem cells-derived insulin-producing cells. Several protocols have been developed over the past couple of years for generating insulin-producing cells (IPCs) from various stem cell types and reprogramming fully differentiated cells. A straightforward and quick method for achieving this goal is to investigate and apply the β-cell specific transcription factors as a direct strategy for IPCs generation. In this review, we emphasize the significance of transcription factors in IPCs development from different non-beta cell sources, and pertinent research underlies the marked progress in the methods for generating insulin-producing cells and application for Type 1 Diabetes treatment.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000801/pdfft?md5=fcdcc5295b330f46c6a2e31f07c9f9d2&pid=1-s2.0-S2472555223000801-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136400717","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":"Characterization and comparison of hypoxia inducing factors on tumor growth and metastasis between two- and three-dimensional cancer models","authors":"Leo Li-Ying Chan ,&nbsp;Sarah L. Kessel ,&nbsp;Bo Lin ,&nbsp;Anna Juncker-Jensen ,&nbsp;Paul Weingarten","doi":"10.1016/j.slasd.2023.10.007","DOIUrl":"10.1016/j.slasd.2023.10.007","url":null,"abstract":"<div><p>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 image cytometer, we identify a hypoxic response in the tumorsphere model that is distinct from that of cells grown under 2-dimensional (2D) normoxic conditions and demonstrate a key role for Mct-4 in enabling 3D growth. The tumorsphere model yields evidence of an essential role for Mct-4 in multiple cell lines, which were genetically modified to underexpress and overexpress Mct-4, evidence not apparent in a standard 2D model of growth in the same cell lines. In addition, we identify the effects of overexpressing Mct-4 in cancer cell migration using a transwell chamber assay. We also show that the response to hypoxia may be circumvented by transfection with a CMV promoter driven Mct-4, which confers constitutive 3D growth, wherein tumorsphere growth inhibition by small molecule HIF-1α inhibitors is mitigated. Finally, we demonstrate quantifiable gene/protein expression differences between 2D and 3D cancer models based on the normoxic and hypoxic conditions. Therefore, the tumorsphere 3D model generated using 384-well ULA plates in combination with high-throughput image cytometer is demonstrated to provide a convenient, robust, and reproducible tool and method for the elucidation of mechanisms of action underlying tumor growth and migration in the hypoxic tumor microenvironment.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223000771/pdfft?md5=177dab2f5907cc4b2a8d24f9e03b04af&pid=1-s2.0-S2472555223000771-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136127865","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":"Micro/nano topological modification of TiO2 nanotubes activates Thy-1 signaling to control osteogenic differentiation of stem cells","authors":"Li Jinsheng ,&nbsp;Deng Qing ,&nbsp;Chen Junhao ,&nbsp;Si Qiqi ,&nbsp;Chen Jieru ,&nbsp;Yang Liwen ,&nbsp;Guo Zhiyun ,&nbsp;Guo Tailin ,&nbsp;Weng Jie","doi":"10.1016/j.slasd.2023.12.011","DOIUrl":"10.1016/j.slasd.2023.12.011","url":null,"abstract":"<div><p>Micro/nano topological modification is critical for improving the in vivo behaviors of bone implants, regulating multiple cellular functions. Titania (TiO₂) nanotubes show the capacity of promoting osteoblast-related cell differentiation and induce effective osseointegration, serving as a model material for studying the effects of micro/nano-topological modifications on cells. However, the intracellular signaling pathways by which TiO₂ nanotubes regulate the osteogenic differentiation of stem cells are not fully defined. Thy-1 (CD90), a cell surface glycoprotein anchored by glycosylphosphatidylinositol, has been considered a key molecule in osteoblast differentiation in recent years. Nevertheless, whether the micro/nano topology of the implant surface leads to changes in Thy-1 is unknown, as well as whether these changes promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Here, TiO₂ nanotubes of various diameters were prepared by adjusting the anodizing voltage. qPCR and immunoblot were carried out to assess the mechanism by which TiO₂ nanotubes regulate Thy-1. The results revealed Ti plates harboring TiO₂ nanotubes ∼100-nm diameter (TNT-100) markedly upregulated Thy-1. Subsequently, upregulated Thy-1 promoted the activation of Fyn/RhoA/MLC Ⅱ/F-actin axis, which enhanced the nuclear translocation of YAP. After Thy-1 knockdown by siRNA, the Fyn/RhoA/MLC Ⅱ/F-actin axis was significantly inhibited and TiO₂ nanotubes showed decreased effects on osteogenic differentiation. Therefore, Thy-1 upregulation might be a major mechanism by which micro/nano-topological modification of TiO₂ nanotubes promotes osteogenic differentiation in BMSCs. This study provides novel insights into the molecular mechanism of TiO₂ nanotubes, which may help design improved bone implants for clinical application.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223001120/pdfft?md5=a5a06a6783815479240aae3965bb25a0&pid=1-s2.0-S2472555223001120-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139063244","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":"FLECS technology for high-throughput screening of hypercontractile cellular phenotypes in fibrosis: A function-first approach to anti-fibrotic drug discovery","authors":"Yao Wang ,&nbsp;Enrico Cortes ,&nbsp;Ricky Huang ,&nbsp;Jeremy Wan ,&nbsp;Junyi Zhao ,&nbsp;Boris Hinz ,&nbsp;Robert Damoiseaux ,&nbsp;Ivan Pushkarsky","doi":"10.1016/j.slasd.2023.12.010","DOIUrl":"10.1016/j.slasd.2023.12.010","url":null,"abstract":"<div><p>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 assay we screened a library of 40,000 novel small molecules in under 80 h of total assay run-time. We identified 42 hit compounds that inhibited the TGF-β1-induced contractile phenotype of myofibroblasts, and enriched for 19 that specifically target myofibroblasts but not phenotypically related smooth muscle cells. Selected hits were validated in an <em>ex vivo</em> lung tissue models for their inhibitory effects on fibrotic gene upregulation by TGF-β1. Our results demonstrate that integrating a functional contraction test into the drug screening process is key to identify compounds with targeted and diverse activity as potential anti-fibrotic agents.</p></div>","PeriodicalId":21764,"journal":{"name":"SLAS Discovery","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2472555223001090/pdfft?md5=26cf5443295c04ca2fa385e66bc86a32&pid=1-s2.0-S2472555223001090-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139063246","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}