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| Status |
Public on Sep 13, 2021 |
| Title |
Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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 3D phenotypic high-content assay and screened a library of FDA/EMA approved small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence (FANTAIL) identified Tranilast as an effective inhibitor, however, by structure-activity relationship studies we found 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 SMAD (de)ubiquitination/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/PAI1 and CXCL8/IL8. Conclusively, these data suggest N23Ps as a novel class of highly potent compounds with implications for inhibiting organ fibrosis in patients.
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| Overall design |
We performed gene expression microarray analysis in primary human pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis. Cells were treated with TGFb1, cmp4 or with a combination of both
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| Contributor(s) |
Gerckens M, Schorpp K, Pelizza F, Wögrath M, Reichau K, Ma H, Dworsky A, Sengupta A, Stoleriu M, Heinzelmann K, Merl-Pham J, Irmler M, Alsafadi HN, Trenkenschuh E, Sarnova L, Jirouskova M, Frieß W, Hauck SM, Beckers J, Kneidinger N, Behr J, Hilgendorff A, Hadian K, Lindner M, Königshoff M, Eickelberg O, Gregor M, Plettenburg O, Yildirim A, Burgstaller G |
| Citation(s) |
34936468 |
| Submission date |
Dec 12, 2019 |
| Last update date |
Dec 29, 2021 |
| Contact name |
Johannes Beckers |
| E-mail(s) |
johannes.beckers@helmholtz-munich.de
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| Organization name |
Helmholtz Zentrum Muenchen
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| Department |
Institute of Experimental Genetics
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| Street address |
Ingolstaedter Landstr. 1
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| City |
Neuherberg |
| ZIP/Postal code |
85764 |
| Country |
Germany |
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| Platforms (1) |
| GPL23159 |
[Clariom_S_Human] Affymetrix Clariom S Assay, Human (Includes Pico Assay) |
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| Samples (12)
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| GSM4215815 |
IPF-derived_primary_lung_fibroblasts_cmp4_rep1 |
| GSM4215816 |
IPF-derived_primary_lung_fibroblasts_cmp4_rep2 |
| GSM4215817 |
IPF-derived_primary_lung_fibroblasts_cmp4_rep3 |
| GSM4215818 |
IPF-derived_primary_lung_fibroblasts_Ctrl_rep1 |
| GSM4215819 |
IPF-derived_primary_lung_fibroblasts_Ctrl_rep2 |
| GSM4215820 |
IPF-derived_primary_lung_fibroblasts_Ctrl_rep3 |
| GSM4215821 |
IPF-derived_primary_lung_fibroblasts_TGFb1_cmp4_rep1 |
| GSM4215822 |
IPF-derived_primary_lung_fibroblasts_TGFb1_cmp4_rep2 |
| GSM4215823 |
IPF-derived_primary_lung_fibroblasts_TGFb1_cmp4_rep3 |
| GSM4215824 |
IPF-derived_primary_lung_fibroblasts_TGFb1_rep1 |
| GSM4215825 |
IPF-derived_primary_lung_fibroblasts_TGFb1_rep2 |
| GSM4215826 |
IPF-derived_primary_lung_fibroblasts_TGFb1_rep3 |
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| Relations |
| BioProject |
PRJNA595156 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE141905_RAW.tar |
13.9 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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