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Gerckens, M. ; Schorpp, K.K. ; Pelizza, F.* ; Wögrath, M. ; Reichau, K. ; Ma, H. ; Dworsky, A.-M. ; Sengupta, A. ; Stoleriu, M.-G. ; Heinzelmann, K. ; Merl-Pham, J. ; Irmler, M. ; Alsafadi, H.N. ; Trenkenschuh, E.* ; Sarnova, L.* ; Jirouskova, M.* ; Frieß, W.* ; Hauck, S.M. ; Beckers, J. ; Kneidinger, N. ; Behr, J. ; Hilgendorff, A. ; Hadian, K. ; Lindner, M. ; Königshoff, M. ; Eickelberg, O.* ; Gregor, M.* ; Plettenburg, O. ; Yildirim, A.Ö. ; Burgstaller, G.

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

Sci. Adv. 7:eabb3673 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag

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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Publication type Article: Journal article
Document type Scientific Article
Keywords Idiopathic Pulmonary-fibrosis; Growth-factor-beta; Selective-inhibition; Acute Exacerbation; Label-free; Proteome; Matrix; Trial; Mechanisms; Tranilast
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Quellenangaben Volume: 7, Issue: 52, Pages: , Article Number: eabb3673 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Grants GACR
MEYS CR
MH CR
CSC graduate fellowship
Helmholtz Alliance "Aging and Metabolic Programming, AMPro"
LMU Munich by Lehre@LMU Forderung
Helmholtz Association
German Center of Lung Research (DZL)