Pneumologie 2019; 73(02): 113-114
DOI: 10.1055/s-0039-1678397
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

High-Throughput Drug Screening of ECM Deposition Inhibitors for Antifibrotic Drug Discovery

Michael Gerckens
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
,
Hani Alsafadi
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
5  Department of Experimental Medical Science, Lund University
,
Darcy Wagner
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
5  Department of Experimental Medical Science, Lund University
,
Katharina Heinzelmann
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
,
Kenji Schorpp
2  Helmholtz Center Munich, Institute for Molecular Toxicology and Pharmacology, Assay Development and Screening Platform
,
Kamyar Hadian
2  Helmholtz Center Munich, Institute for Molecular Toxicology and Pharmacology, Assay Development and Screening Platform
,
Michael Lindner
3  Asklepios Fachkliniken Gauting
,
Jürgen Behr
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
3  Asklepios Fachkliniken Gauting
,
Melanie Königshoff
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
4  Division of Respiratory Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA
,
Oliver Eickelberg
4  Division of Respiratory Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA
,
Ali Önder Yildirim
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
,
Gerald Burgstaller
1  Comprehensive Pneumology Center (CPC), Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University, Munich, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
15 February 2019 (online)

 

Idiopathic lung fibrosis (IPF) is a progressive interstitial lung disease with a median patient survival of 3 – 5 years. Up to now, no approved pharmacotherapeutic is able to stop the disease progression in IPF patients. Therefore, the discovery of novel potential IPF therapeutics represents a major medical need. A growing body of evidence indicates a pivotal role of excessive altered ECM deposition in IPF, which is driving disease progression and loss of lung function. We developed a new phenotypic high-throughput drug discovery assay for identifying novel fibrotic ECM deposition inhibitors. Primary IPF patient derived lung fibroblasts were activated by transforming growth factor β (TGFβ1) to trigger transdifferentiation into myofibroblasts and a concomitant increase in ECM deposition, both of which are defining hallmarks of IPF. Live immunolabeling of deposited ECM molecules and an automated confocal imaging in a 384-well plate format, coupled to an automated 3D image analysis, resulted in a confident assessment of the alterations in the ECMʼs deposition. Subsequent screening 1039 FDA/EMA approved drugs (Prestwick library) resulted in the identification of potential 22 ECM-deposition-inhibitors for drug repurposing. These hits clustered in drug classes, including cardiac glycosides and ACE inhibitors. In conclusion, we established a phenotypic screening pipeline for the discovery of novel potential antifibrotic pharmacotherapeutics and performed a proof-of-concept study. The identified drug candidates will be further validated in a fibrotic ex-vivo tissue culture system of human precision-cut-lung slices (PCLS) to select the best candidates for an in-vivo validation in a fibrosis animal model. In conclusion, we strongly believe that our innovative approach opens new paths for an unbiased antifibrotic drug discovery and furthermore is apt for the screening of large small molecule based libraries.