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AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease

BACKGROUND: To examine therapeutic effect of TEW-7197, a novel small molecule inhibitor of activin receptor-like kinase 5 (ALK5), in an animal model of Peyronie’s disease (PD) and to determine mechanisms by which TEW-7197 ameliorates fibrotic responses in primary fibroblasts derived from human PD pl...

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Autores principales: Song, Kang-Moon, Choi, Min Ji, Ghatak, Kalyan, Minh, Nguyen Nhat, Kwon, Mi-Hye, Ock, Jiyeon, Yin, Guo Nan, Ryu, Ji-Kan, Suh, Jun-Kyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186741/
http://dx.doi.org/10.21037/tau.2018.AB083
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author Song, Kang-Moon
Choi, Min Ji
Ghatak, Kalyan
Minh, Nguyen Nhat
Kwon, Mi-Hye
Ock, Jiyeon
Yin, Guo Nan
Ryu, Ji-Kan
Suh, Jun-Kyu
author_facet Song, Kang-Moon
Choi, Min Ji
Ghatak, Kalyan
Minh, Nguyen Nhat
Kwon, Mi-Hye
Ock, Jiyeon
Yin, Guo Nan
Ryu, Ji-Kan
Suh, Jun-Kyu
author_sort Song, Kang-Moon
collection PubMed
description BACKGROUND: To examine therapeutic effect of TEW-7197, a novel small molecule inhibitor of activin receptor-like kinase 5 (ALK5), in an animal model of Peyronie’s disease (PD) and to determine mechanisms by which TEW-7197 ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque. METHODS: Rats were distributed into 3 groups (N=6 per group): age-matched controls without treatment; PD rats receiving vehicle; and PD rats receiving TEW-7197 (10 mg/kg). PD-like plaque was induced by repeated intratunical injections of 100 µL of each of human fibrin and thrombin solutions on days 0 and 5. TEW-7197 was given orally five times a week for 2 weeks. On day 30, erectile function was measured during the electrical stimulation of the cavernous nerve, and the penis was then harvested for histologic examination. Fibroblasts isolated from human PD plaque were used to determine anti-fibrotic effects of TEW-7197 in vitro. RESULTS: TEW-7197 induced significant regression of fibrotic plaque in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which resulted in a recovery of erectile function. TEW-7197 also abrogated TGF-β1-induced enhancement in extracellular matrix production and hydroxyproline content in PD fibroblast in vitro by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. CONCLUSIONS: In view of the critical role of TGF-β and Smad pathway in the pathogenesis of PD, antagonizing this pathway through the use of ALK5 inhibitor may represent a novel targeted therapy for PD.
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spelling pubmed-61867412018-10-26 AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease Song, Kang-Moon Choi, Min Ji Ghatak, Kalyan Minh, Nguyen Nhat Kwon, Mi-Hye Ock, Jiyeon Yin, Guo Nan Ryu, Ji-Kan Suh, Jun-Kyu Transl Androl Urol Printed Abstract BACKGROUND: To examine therapeutic effect of TEW-7197, a novel small molecule inhibitor of activin receptor-like kinase 5 (ALK5), in an animal model of Peyronie’s disease (PD) and to determine mechanisms by which TEW-7197 ameliorates fibrotic responses in primary fibroblasts derived from human PD plaque. METHODS: Rats were distributed into 3 groups (N=6 per group): age-matched controls without treatment; PD rats receiving vehicle; and PD rats receiving TEW-7197 (10 mg/kg). PD-like plaque was induced by repeated intratunical injections of 100 µL of each of human fibrin and thrombin solutions on days 0 and 5. TEW-7197 was given orally five times a week for 2 weeks. On day 30, erectile function was measured during the electrical stimulation of the cavernous nerve, and the penis was then harvested for histologic examination. Fibroblasts isolated from human PD plaque were used to determine anti-fibrotic effects of TEW-7197 in vitro. RESULTS: TEW-7197 induced significant regression of fibrotic plaque in PD rats in vivo through reduced infiltration of inflammatory cells and reduced expression of phospho-Smad2, which resulted in a recovery of erectile function. TEW-7197 also abrogated TGF-β1-induced enhancement in extracellular matrix production and hydroxyproline content in PD fibroblast in vitro by blocking TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3, and by inhibiting TGF-β1-induced transdifferentiation of fibroblasts into myofibroblasts. CONCLUSIONS: In view of the critical role of TGF-β and Smad pathway in the pathogenesis of PD, antagonizing this pathway through the use of ALK5 inhibitor may represent a novel targeted therapy for PD. AME Publishing Company 2018-09 /pmc/articles/PMC6186741/ http://dx.doi.org/10.21037/tau.2018.AB083 Text en 2018 Translational Andrology and Urology. All rights reserved.
spellingShingle Printed Abstract
Song, Kang-Moon
Choi, Min Ji
Ghatak, Kalyan
Minh, Nguyen Nhat
Kwon, Mi-Hye
Ock, Jiyeon
Yin, Guo Nan
Ryu, Ji-Kan
Suh, Jun-Kyu
AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title_full AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title_fullStr AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title_full_unstemmed AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title_short AB083. TEW-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of Peyronie’s disease
title_sort ab083. tew-7197, a novel orally bioavailable activin receptor-like kinase 5 inhibitor, promotes regression of fibrotic plaque in a rat model of peyronie’s disease
topic Printed Abstract
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186741/
http://dx.doi.org/10.21037/tau.2018.AB083
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