Saracatinib, a Selective Src Kinase Inhibitor, Blocks Fibrotic Responses in In Vitro, In Vivo and Ex Vivo Models of Pulmonary Fibrosis
Year: 2022
Type: preprint
Abstract: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and often fatal disorder. Two FDA approved anti-fibrotic drugs, nintedanib and pirfenidone, slow the rate of decline in lung function, but responses are variable and side effects are common. Using an in-silico data-driven approach, we identified a robust connection between the transcriptomic perturbations in IPF disease and those induced by saracatinib, a selective Src kinase inhibitor, originally developed for oncological indications. Based on these observations, we hypothesized that saracatinib would be effective at attenuating pulmonary fibrosis. We investigated the anti-fibrotic efficacy of saracatinib relative to nintedanib and pirfenidone in three preclinical models: (i) in vitro in normal human lung fibroblasts (NHLFs); (ii) in vivo in bleomycin and recombinant adenovirus transforming growth factor-beta (Ad-TGF-β) murine models of pulmonary fibrosis; and (iii) ex vivo in precision cut lung slices from these mouse models. In each model, the effectiveness of saracatinib in blocking fibrogenic responses was equal or superior to nintedanib and pirfenidone.
Authors: Farida Ahangari, Christine Becker, Daniel G. Foster, Maurizio Chioccioli, Meghan Nelson, Keriann Beke, Xing Wang, Benjamin Readhead, Carly Meador, Kelly Correll, Loukia Lili, Helen M. Roybal, Kadi-Ann Rose, Shuizi Ding, Thomas Barnthaler, Natalie Briones, Giuseppe Deluliis, Jonas C. Schupp, Qin Li, Norihito Omote, Yael Aschner, Katrina W. Kopf, Björn Magnusson, Ryan Hicks, Anna Backmark, Leslie P. Cousens, Joel T. Dudley, Naftali Kaminski, Gregory P. Downey
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Use of the Src Family Kinase Inhibitor Saracatinib in the Treatment of Pulmonary Fibrosis, Center for causal Modeling and discovery of Biomedical Knowledge from Big Data, Alveolar DevMAP, Normal Aging Lung Cell Atlas (NALCA), Checkpoint Function of PTPalpha in Pathological Fibrogenesis in the Lung, Genomic Analysis of Tissue and Cellular Heterogeneity in IPF
OpenAlex ID: W4205335764