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

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Michael Gerckens
  • Kenji Schorpp
  • Francesco Pelizza
  • Melanie Wögrath
  • Kora Reichau
  • Huilong Ma
  • Armando Marco Dworsky
  • Arunima Sengupta
  • Mircea Gabriel Stoleriu
  • Katharina Heinzelmann
  • Juliane Merl-Pham
  • Martin Irmler
  • Hani N. Alsafadi
  • Eduard Trenkenschuh
  • Lenka Sarnova
  • Marketa Jirouskova
  • Wolfgang Frieß
  • Stefanie M. Hauck
  • Johannes Beckers
  • Nikolaus Kneidinger
  • Jürgen Behr
  • Anne Hilgendorff
  • Kamyar Hadian
  • Michael Lindner
  • Melanie Königshoff
  • Oliver Eickelberg
  • Martin Gregor
  • Oliver Plettenburg
  • Ali Önder Yildirim
  • Gerald Burgstaller

External Research Organisations

  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • University of Strathclyde
  • Asklepios Fachkliniken Munich-Gauting
  • University of Pittsburgh
  • Ludwig-Maximilians-Universität München (LMU)
  • Czech Academy of Sciences (CAS)
  • German Center for Diabetes Research (DZD)
  • Technical University of Munich (TUM)
  • Paracelsus Private Medical University
  • Justus Liebig University Giessen
  • Lund University
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Details

Original languageEnglish
Article numbereabb3673
JournalScience advances
Volume7
Issue number52
Publication statusPublished - 22 Dec 2021

Abstract

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.

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. / Gerckens, Michael; Schorpp, Kenji; Pelizza, Francesco et al.
In: Science advances, Vol. 7, No. 52, eabb3673, 22.12.2021.

Research output: Contribution to journalArticleResearchpeer review

Gerckens, M, Schorpp, K, Pelizza, F, Wögrath, M, Reichau, K, Ma, H, Dworsky, AM, Sengupta, A, Stoleriu, MG, 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, AÖ & Burgstaller, G 2021, 'Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics', Science advances, vol. 7, no. 52, eabb3673. https://doi.org/10.1126/sciadv.abb3673
Gerckens, M., Schorpp, 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., ... Burgstaller, G. (2021). Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. Science advances, 7(52), Article eabb3673. https://doi.org/10.1126/sciadv.abb3673
Gerckens M, Schorpp K, Pelizza F, Wögrath M, Reichau K, Ma H et al. Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. Science advances. 2021 Dec 22;7(52):eabb3673. doi: 10.1126/sciadv.abb3673
Gerckens, Michael ; Schorpp, Kenji ; Pelizza, Francesco et al. / Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics. In: Science advances. 2021 ; Vol. 7, No. 52.
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title = "Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics",
abstract = "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. ",
author = "Michael Gerckens and Kenji Schorpp and Francesco Pelizza and Melanie W{\"o}grath and Kora Reichau and Huilong Ma and Dworsky, {Armando Marco} and Arunima Sengupta and Stoleriu, {Mircea Gabriel} and Katharina Heinzelmann and Juliane Merl-Pham and Martin Irmler and Alsafadi, {Hani N.} and Eduard Trenkenschuh and Lenka Sarnova and Marketa Jirouskova and Wolfgang Frie{\ss} and Hauck, {Stefanie M.} and Johannes Beckers and Nikolaus Kneidinger and J{\"u}rgen Behr and Anne Hilgendorff and Kamyar Hadian and Michael Lindner and Melanie K{\"o}nigshoff and Oliver Eickelberg and Martin Gregor and Oliver Plettenburg and Yildirim, {Ali {\"O}nder} and Gerald Burgstaller",
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Download

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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

N1 - Funding Information: This work was supported by the German Center of Lung Research (DZL), the Helmholtz Association, the LMU Munich by Lehre@LMU Förderung to M.G., and the Helmholtz Alliance "Aging and Metabolic Programming, AMPro" (to J.Bec.). H.M. acknowledges a CSC graduate fellowship. M.Gr. reports the following funding grants: MH CR (grant 17-31538A) and MEYS CR (grant LQ1604). M.J. acknowledges GACR funding (grant 18-02699S).

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.

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DO - 10.1126/sciadv.abb3673

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AN - SCOPUS:85122002670

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