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Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics
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SYSNO ASEP 0554604 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics Author(s) Gerckens, M. (DE)
Sarnová, Lenka (UMG-J)
Jiroušková, Markéta (UMG-J) RID, ORCID
Gregor, Martin (UMG-J) RID, ORCID
Burgstaller, G. (DE)Number of authors 30 Article number eabb3673 Source Title Science Advances. - : American Association for the Advancement of Science - ISSN 2375-2548
Roč. 7, č. 52 (2021)Number of pages 19 s. Publication form Online - E Language eng - English Country US - United States Keywords idiopathic pulmonary-fibrosis ; growth-factor-beta ; selective-inhibition ; acute exacerbation ; label-free ; proteome ; matrix ; trial ; mechanisms ; tranilast Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects NV17-31538A GA MZd - Ministry of Health (MZ) LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA18-02699S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000733258700009 DOI 10.1126/sciadv.abb3673 Annotation Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced three-dimensional phenotypic high-content assay and screened a repurposing drug library of small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence identified tranilast as an effective inhibitor. Structure-activity relationship studies confirmed N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMURF2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1 and CXCL8. Conclusively, N23Ps are a novel class of highly potent compounds inhibiting organ fibrosis in patients. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2022 Electronic address https://www.science.org/doi/10.1126/sciadv.abb3673
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