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.
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.
Ryu
Ji-Kan
JK
Department of Urology and Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon 400-711, Korea.
Piao
Shuguang
S
Shin
Hwa-Yean
HY
Choi
Min Ji
MJ
Zhang
Lu Wei
LW
Jin
Hai-Rong
HR
Kim
Woo Jean
WJ
Han
Jee-Young
JY
Hong
Soon Sun
SS
Park
Seok Hee
SH
Lee
Sang-Jin
SJ
Kim
In-Hoo
IH
Lee
Chung Ryul
CR
Kim
Dae-Kee
DK
Mamura
Mizuko
M
Kim
Seong-Jin
SJ
Suh
Jun-Kyu
JK
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
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