IN-1130, a novel transforming growth factor-β type I receptor kinase (Activin Receptor-like Kinase 5) inhibitor, promotes regression of fibrotic plaque and corrects penile curvature in a rat model of Peyronie's disease

Ji Kan Ryu, Shuguang Piao, Hwa Yean Shin, Min Ji Choi, Lu Wei Zhang, Hai Rong Jin, Woo Jean Kim, Jee Young Han, Soon Sun Hong, Seok Hee Park, Sang Jin Lee, In Hoo Kim, Chung Ryul Lee, Dae Kee Kim, Mizuko Mamura, Seong Jin Kim, Jun Kyu Suh

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37 Scopus citations

Abstract

Introduction. Transforming growth factor-β1 (TGF-β1) has been known to play a crucial role in the pathogenesis of Peyronie's disease (PD). Aim. The aim of this paper was to investigate the therapeutic effect of IN-1130, a novel small molecule inhibitor of activin receptor-like kinase (ALK)5, a type I receptor of TGF-β, in an animal model of PD. Methods. PD was induced in rats through repeated injections of adenovirus expressing TGF-β1 (days 0, 3, and 6; 1 × 10 10 particles/0.1mL, respectively) into the tunica albuginea. The rats were divided into five groups (N = 10 per group): group 1, age-matched controls without treatment; group 2, age-matched controls receiving repeated injections of IN-1130 (days 30 and 37; 5 mg/kg in 0.1mL saline, respectively); group 3, PD rats without treatment; group 4, PD rats receiving repeated injections of saline (days 30 and 37; 0.1mL, respectively); group 5, PD rats receiving repeated injections of IN-1130 (days 30 and 37; 5 mg/kg in 0.1 mL saline, respectively) into the lesion. Main Outcome Measures. Penile curvature was evaluated by use ofan artificial erection test at day 45, and the penis was then harvested for histologic examination. Collagen in the plaque was quantitatively assessed by hydroxyproline determination. Results. IN-1130 induced significant regression of fibrotic plaque through reduced infiltration of inflammatory cells, reduced transnuclear expression of phospho-Smad2/phospho-Smad3, reduced hydroxyproline content, and reduced cartilage content and restoration of elastin fibers in the fibrotic plaque of PD rats, which was accompanied by the correction of penile curvature. Conclusion. Antagonizing TGF-β signaling through the use of ALK5 inhibitors may represent an exciting new therapeutic strategy for the future treatment of PD.

Original languageEnglish
Pages (from-to)1284-1296
Number of pages13
JournalJournal of Sexual Medicine
Volume6
Issue number5
DOIs
StatePublished - 2009

Keywords

  • ALK5
  • Fibrosis
  • IN-1130
  • Peyronie's disease
  • Transforming growth factor-beta

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