Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics

Gerckens, Michael and Schorpp, Kenji and Pelizza, Francesco and Wögrath, Melanie and Reichau, Kora and Ma, Huilong and Dworsky, Armando-Marco and Sengupta, Arunima and Stoleriu, Mircea Gabriel and Heinzelmann, Katharina and Merl-Pham, Juliane and Irmler, Martin and Alsafadi, Hani N and Trenkenschuh, Eduard and Sarnova, Lenka and Jirouskova, Marketa and Frieß, Wolfgang and Hauck, Stefanie M and Beckers, Johannes and Kneidinger, Nikolaus and Behr, Jürgen and Hilgendorff, Anne and Hadian, Kamyar and Lindner, Michael and Königshoff, Melanie and Eickelberg, Oliver and Gregor, Martin and Plettenburg, Oliver and Yildirim, Ali Önder and Burgstaller, Gerald (2021) Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. Science Advances, 7 (52). eabb3673. ISSN 2375-2548 (

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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.