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

Michael GerckensKenji SchorppFrancesco PelizzaMelanie WögrathKora ReichauHuilong MaArmando-Marco DworskyArunima SenguptaMircea-Gabriel StoleriuKatharina HeinzelmannJuliane Merl-PhamMartin IrmlerHani N AlsafadiEduard TrenkenschuhLenka SarnovaMarketa JirouskovaWolfgang FriessStefanie M HauckJohannes BeckersNikolaus KneidingerJuergen BehrAnne HilgendorffKamyar HadianMichael LindnerMelanie KönigshoffOliver EickelbergMartin GregorOliver PlettenburgAli Oender YildirimGerald Burgstaller
Published in: Science advances (2021)
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.
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