SM16, an orally active TGF-beta type I receptor inhibitor prevents myofibroblast induction and vascular fibrosis in the rat carotid injury model.
OBJECTIVE
TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis.


RESULTS
The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells.


CONCLUSIONS
These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.
Fu
Kai
K
Department of Pharmacology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA.
Corbley
Michael J
MJ
Sun
Lihong
L
Friedman
Jessica E
JE
Shan
Feng
F
Papadatos
James L
JL
Costa
Donald
D
Lutterodt
Frank
F
Sweigard
Harry
H
Bowes
Scott
S
Choi
Michael
M
Boriack-Sjodin
P Ann
PA
Arduini
Robert M
RM
Sun
Dongyu
D
Newman
Miki N
MN
Zhang
Xiamei
X
Mead
Jonathan N
JN
Chuaqui
Claudio E
CE
Cheung
H-Kam
HK
Zhang
Xin
X
Cornebise
Mark
M
Carter
Mary Beth
MB
Josiah
Serene
S
Singh
Juswinder
J
Lee
Wen-Cherng
WC
Gill
Alan
A
Ling
Leona E
LE
D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008297:Male; D032390:Myoblasts, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000502:physiology
D053961:Azabicyclo Compounds; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C528106:SM16 compound; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat