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

Michael Gerckens, Kenji Schorpp, Francesco Pelizza, Melanie Wögrath, Kora Reichau, Huilong Ma, Armando Marco Dworsky, Arunima Sengupta, Mircea Gabriel Stoleriu, Katharina Heinzelmann, Juliane Merl-Pham, Martin Irmler, Hani N. Alsafadi, Eduard Trenkenschuh, Lenka Sarnova, Marketa Jirouskova, Wolfgang Frieß, Stefanie M. Hauck, Johannes Beckers, Nikolaus KneidingerJürgen Behr, Anne Hilgendorff, Kamyar Hadian, Michael Lindner, Melanie Königshoff, Oliver Eickelberg, Martin Gregor, Oliver Plettenburg, Ali Önder Yildirim, Gerald Burgstaller

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Article numbereabb3673
JournalScience Advances
Issue number52
StatePublished - Dec 2021


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