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Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation
- Source :
- Cell Death and Disease, Vol 13, Iss 1, Pp 1-12 (2021), Cell Death & Disease
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- SummaryTherapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis.
- Subjects :
- High-Throughput Screening Assay
Lung Diseases
Pulmonary fibrosis
idiopathic pulmonary fibrosis
fibroblasta
myofibroblasts
bleomycin mouse model
high-throughput sceening
TS1
Cancer Research
Immunology
Transfection
Lung Disease
Article
Machine Learning
Bleomycin
Mice
Cellular and Molecular Neuroscience
Animals
Humans
Myofibroblast
Respiratory tract diseases
QH573-671
idiopathic pulmonary fibrosi
Animal
Drug discovery
Idiopathic Pulmonary Fibrosi
Cell Differentiation
Cell Biology
myofibroblast
High-Throughput Screening Assays
Drug Screening Assays, Antitumor
Cytology
Pulmonary fibrosi
Human
Subjects
Details
- ISSN :
- 20414889
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Cell Death & Disease
- Accession number :
- edsair.doi.dedup.....705a3ff684c035c71c480b59cb791836