title: IN-1130, a novel transforming growth factor-beta 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.
abstract: BACKGROUND
  Transforming growth factor-beta1 (TGF-beta1) has been known to play a crucial role in the pathogenesis of Peyronie's disease (PD).
  
  
  OBJECTIVE
  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-beta, in an animal model of PD.
  
  
  METHODS
  PD was induced in rats through repeated injections of adenovirus expressing TGF-beta1 (days 0, 3, and 6; 1 x 10(10) particles/0.1 mL, 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 0.1 mL saline, respectively); group 3, PD rats without treatment; group 4, PD rats receiving repeated injections of saline (days 30 and 37; 0.1 mL, 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.
  
  
  METHODS
  Penile curvature was evaluated by use of an 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.
  
  
  CONCLUSIONS
  Antagonizing TGF-beta signaling through the use of ALK5 inhibitors may represent an exciting new therapeutic strategy for the future treatment of PD.
authors.affiliation: Department of Urology and Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon 400-711, Korea.
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.forename: Shuguang
authors.initials: S
authors.lastname: Piao
authors.forename: Hwa-Yean
authors.initials: HY
authors.lastname: Shin
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Lu Wei
authors.initials: LW
authors.lastname: Zhang
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Jin
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Jee-Young
authors.initials: JY
authors.lastname: Han
authors.forename: Soon Sun
authors.initials: SS
authors.lastname: Hong
authors.forename: Seok Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: In-Hoo
authors.initials: IH
authors.lastname: Kim
authors.forename: Chung Ryul
authors.initials: CR
authors.lastname: Lee
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D010411:Penile Induration / Q000188:drug therapy* / Q000473:pathology; D010413:Penis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011810:Quinoxalines / Q000008:administration & dosage*; D051381:Rats
chemical_list: C530153:3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines