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 Sarnová, Markéta Jiroušková, Wolfgang Frieß, Stefanie M. Hauck, Johannes Beckers, Nikolaus Kneidinger, Jürgen Behr, Anne Hilgendorff, Kamyar Hadian, Michael Lindner, Mélanie Königshoff, Oliver Eickelberg, Martin Gregor, Oliver Plettenburg, Ali Önder Yildirim, Gerald Burgstaller
Abstract
-(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.