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

0554604 - ÚMG 2022 RIV US eng J - Journal Article
Gerckens, M. - Sarnová, Lenka - Jiroušková, Markéta - Gregor, Martin - Burgstaller, G. … Total 30 authors
Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.
Science Advances. Roč. 7, č. 52 (2021), č. článku eabb3673. ISSN 2375-2548. E-ISSN 2375-2548
R&D Projects: GA MZd NV17-31538A; GA MŠMT(CZ) LQ1604; GA ČR GA18-02699S
Institutional support: RVO:68378050
Keywords : idiopathic pulmonary-fibrosis * growth-factor-beta * selective-inhibition * acute exacerbation * label-free * proteome * matrix * trial * mechanisms * tranilast
OECD category: Cell biology
Impact factor: 14.980, year: 2021
Method of publishing: Open access
https://www.science.org/doi/10.1126/sciadv.abb3673

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.
Permanent Link: http://hdl.handle.net/11104/0329307