title: IM-412 inhibits transforming growth factor beta-induced fibroblast differentiation in human lung fibroblast cells.
abstract: Pulmonary fibrosis is a type of interstitial lung disease that causes progressive scarring in lung tissues. Although there have been many studies on fibrosis, there is no standard treatment for fibrotic disease. Thus, there is an urgent need for the development of effective anti-fibrotic drugs. Transforming growth factor beta (TGF-beta) is a major fibrotic mediator known to stimulate fibrosis. To identify small molecules that inhibit TGF-beta responses, we performed cell-based chemical screening using genetically engineered HEK293 reporter cells. Among 8000 chemical compounds containing biologically active natural products and synthetic or clinically used compounds, we found that 3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (IM-412) significantly decreased TGF-beta stimulated reporter activity in a dose-dependent manner. In addition, IM-412 inhibited TGF-beta-induced expression of the fibrotic markers alpha-smooth muscle actin (alpha-SMA) and fibronectin, and collagen accumulation in CCD-18Lu human normal lung fibroblasts without cell cytotoxicity. IM-412 decreased Smad2 and -3 phosphorylation as well as JNK and ERK activity. Moreover, expression levels of TGF-beta receptor I (TbetaRI) and receptor II (TbetaRII) were down-regulated by IM-412 in a dose-dependent manner. Thus, our findings indicate that the small molecule IM-412 attenuated TGF-beta-mediated fibroblast differentiation through inhibition of the overall TGF-beta response and may be a promising novel agent for the treatment of pathological fibrotic conditions.
authors.affiliation: Laboratory of Radiation Sensitization & Protection, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Sarah
authors.initials: S
authors.lastname: Park
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Ahn
authors.forename: Min-Jin
authors.initials: MJ
authors.lastname: Lim
authors.forename: Mi-Hyoung
authors.initials: MH
authors.lastname: Kim
authors.forename: Sae-Lo-Oom
authors.initials: SL
authors.lastname: Lee
authors.forename: Yeon-Sook
authors.initials: YS
authors.lastname: Yun
authors.forename: Gajin
authors.initials: G
authors.lastname: Jeong
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D011687:Purines / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology
chemical_list: C552121:3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo(2,1-f)purine-2,4(3H,8H)-dione; D007093:Imidazoles; D011687:Purines; D016212:Transforming Growth Factor beta