Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis.
Proc Natl Acad Sci U S A
; 114(18): 4679-4684, 2017 05 02.
Article
em En
| MEDLINE
| ID: mdl-28416697
ABSTRACT
Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fibrose Pulmonar
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Dermatopatias
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Itraconazol
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Transdiferenciação Celular
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Células Estreladas do Fígado
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Miofibroblastos
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Cirrose Hepática
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article