TY - JOUR
T1 - Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics
AU - Gerckens, Michael
AU - Schorpp, Kenji
AU - Pelizza, Francesco
AU - Wögrath, Melanie
AU - Reichau, Kora
AU - Ma, Huilong
AU - Dworsky, Armando-Marco
AU - Sengupta, Arunima
AU - Stoleriu, Mircea Gabriel
AU - Heinzelmann, Katharina
AU - Merl-Pham, Juliane
AU - Irmler, Martin
AU - Alsafadi, Hani N
AU - Trenkenschuh, Eduard
AU - Sarnova, Lenka
AU - Jirouskova, Marketa
AU - Frieß, Wolfgang
AU - Hauck, Stefanie M
AU - Beckers, Johannes
AU - Kneidinger, Nikolaus
AU - Behr, Jürgen
AU - Hilgendorff, Anne
AU - Hadian, Kamyar
AU - Lindner, Michael
AU - Königshoff, Melanie
AU - Eickelberg, Oliver
AU - Gregor, Martin
AU - Plettenburg, Oliver
AU - Yildirim, Ali Önder
AU - Burgstaller, Gerald
PY - 2021/12/22
Y1 - 2021/12/22
N2 - 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.
AB - 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.
KW - fibrotic diseases
KW - phenotypic drug screening
KW - antifibrotic therapeutics
KW - extracellular matrix (ECM)
U2 - 10.1126/sciadv.abb3673
DO - 10.1126/sciadv.abb3673
M3 - Article
C2 - 34936468
SN - 2375-2548
VL - 7
JO - Science Advances
JF - Science Advances
IS - 52
M1 - eabb3673
ER -
