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Small molecule-mediated inhibition of myofibroblast transdifferentiation for the
treatment of fibrosis
#MMPMID28416697
Bollong MJ
; Yang B
; Vergani N
; Beyer BA
; Chin EN
; Zambaldo C
; Wang D
; Chatterjee AK
; Lairson LL
; Schultz PG
Proc Natl Acad Sci U S A
2017[May]; 114
(18
): 4679-4684
PMID28416697
show ga
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.
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