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

Sci Adv. 2021 Dec 24;7(52):eabb3673. doi: 10.1126/sciadv.abb3673.

Michael Gerckens ¹, Kenji Schorpp ², Francesco Pelizza ³, Melanie Wögrath ¹ ⁴, Kora Reichau ⁵ ⁶, Huilong Ma ⁵ ⁶, Armando-Marco Dworsky ¹ ⁴, Arunima Sengupta ¹, Mircea Gabriel Stoleriu ¹ ⁴ ⁷, Katharina Heinzelmann ⁸ ⁹, Juliane Merl-Pham ¹⁰, Martin Irmler ¹¹, Hani N Alsafadi ⁴ ⁹ ¹², Eduard Trenkenschuh ¹³, Lenka Sarnova ¹⁴, Marketa Jirouskova ¹⁴, Wolfgang Frieß ¹³, Stefanie M Hauck ¹⁰, Johannes Beckers ¹¹ ¹⁵ ¹⁶, Nikolaus Kneidinger ⁴ ¹⁷, Jürgen Behr ⁴ ⁷ ¹⁷, Anne Hilgendorff ¹ ⁴, Kamyar Hadian ², Michael Lindner ⁴ ⁷ ¹⁸, Melanie Königshoff ⁸ ⁹, Oliver Eickelberg ⁸, Martin Gregor ¹⁴, Oliver Plettenburg ⁵ ⁶ ¹⁹, Ali Önder Yildirim ¹, Gerald Burgstaller ¹ ⁴

Affiliations

1 Institute of Lung Biology and Disease (ILBD) and Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
2 Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
3 Chemical and Process Engineering, Strathclyde University, Glasgow, Scotland, UK.
4 CPC-M bioArchive, Helmholtz Zentrum München, Comprehensive Pneumology Center Munich DZL/CPC-M, Munich, Germany.
5 Institute of Medicinal Chemistry, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
6 Leibniz Universität Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research (BMWZ), Hannover, Germany.
7 Asklepios Fachkliniken Munich-Gauting, Munich, Germany.
8 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
9 Comprehensive Pneumology Center (CPC), Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
10 Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
11 Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
12 Wallenberg Center for Molecular Medicine (WCMM), Department of Experimental Medical Sciences, Lund University, Lund, Sweden.
13 Department of Pharmacy-Center for Drug Research, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximillians University of Munich, Munich, Germany.
14 Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
15 German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany.
16 Chair of Experimental Genetics, Technische Universität München, 85354 Freising, Germany.
17 Department of Internal Medicine V, Ludwig-Maximillians University of Munich, Member of the German Center for Lung Research (DZL), Munich, Germany.
18 Paracelsus Medical Private University, Salzburg, Austria.
19 Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.

PMID: 34936468 DOI: 10.1126/sciadv.abb3673

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.

Products

Cat. No.

Product Name

Category/Application
HY-L022

FDA-Approved Drug Library

Drug Repurposing Series

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