Background
LDN193189 is a selective transcriptional activity?morphogenetic protein (BMP) type I receptors inhibitor. It inhibits activin receptor-like kinase-2 (ALK2) and ALK3 with IC50 values of 5 nM and 30 nM, respectively [1].
LDN193189 has been showed to inhibit BMP induced phosphorylation of Smad signaling (Smad1/5/8) and non-Smad signaling including p38 and Akt in C2C12 cells [2].
Pharmacological inhibition of BMP by LDN193189 has shown to prevent down-regulation of E-cadherin in response to BMP2 both in bronchial epithelial (Beas2B) cells and in C57BL/6 mice. LDN193189 also inhibits the BMP-induced reduction of epithelial permeability at cellular level [3].
LDN193189是一种选择性转录活性形态发生蛋白（BMP）类型I受体抑制剂。它以5 nM和30 nM的IC50值抑制激动剂受体样激酶-2（ALK2）和ALK3，分别[1]。
研究表明，LDN193189能够抑制C2C12细胞中BMP诱导的Smad信号通路（Smad1/5/8）和非Smad信号通路，包括p38和Akt的磷酸化[2]。
药理学上通过LDN193189对BMP进行抑制可以防止BMP2诱导的E-cadherin下调反应在支气管上皮细胞（Beas2B）和C57BL/6小鼠中的出现。LDN193189还可以在细胞水平上抑制BMP诱导的上皮通透性降低[3]。
参考文献:
[1] Yu PB,?Deng DY,?Lai CS,?Hong CC,?Cuny GD,?Bouxsein ML,?Hong DW,?McManus PM,?Katagiri T,?Sachidanandan C,?Kamiya N,?Fukuda T,?Mishina Y,?Peterson RT,?Bloch KD. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med.?2008 Dec;14(12):1363-9.
[2] Boergermann JH1,?Kopf J,?Yu PB,?Knaus P. Dorsomorphin and LDN-193189 inhibit BMP-mediated Smad, p38 and Akt signalling in C2C12 cells. Int J Biochem Cell Biol.?2010 Nov;42(11):1802-7.
[3] Helbing T1,?Herold EM,?Hornstein A,?Wintrich S,?Heinke J,?Grundmann S,?Patterson C,?Bode C,?Moser M. Inhibition of BMP activity protects epithelial barrier function in lung injury. J Pathol.?2013 Sep;231(1):105-16. doi: 10.1002/path.4215. Epub 2013 Jul 10.
Protocol
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Cell experiment [1]:
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Cell lines
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C2C12 myofibroblast cells; bronchial epithelial (Beas2B) cells
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Preparation method
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This compound is limited soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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0.005-5 μM. 30-60 min
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Applications
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LDN-193189 inhibited both BMP induced Smad1/5/8 phosphorylation and BMP-mediated induction of the p38 MAPK, Erk1/2 and Akt pathway in C2C12 cells. LDN-193189 dose-dependently inhibited the activation of Smad1/5/8, p38 and Akt. LDN-193189 induced a strong increase in phosphorylated p38 MAPK levels and a slight increase in p-Akt in C2C12 cells. LDN (10 μM, 60 min) induced p38 and Akt phosphorylation. LDN (0.5 μM, 30 min) inhibited BMP-mediated Smad1/5/8, p38, ATF2 and CREB phosphorylation.
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Animal experiment [2]:
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Animal models
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C57BL/6 mice
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Dosage form
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Intraperitoneal injection; 3 mg/kg every 12 h
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Application
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In Ad.Cre-injected, caALK2-expressing mice, treatment with LDN-193189 prevented radiographic lesions at P15. LDN-193189–treated mice appeared to preserve knee and ankle joints at P30 and P60. LDN-193189-treated mice showed no ectopic bone at P15 but did show enhanced cartilage formation in surrounding soft tissues. LDN-193189–treated mice showed mildly impaired range of motion even in the absence of radiographically visible disease at P30.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Kamiya N, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med. 2008 Dec;14(12):1363-9.
[2]. Yu PB, Deng DY, Lai CS, Hong CC, Cuny GD, Bouxsein ML, Hong DW, McManus PM, Katagiri T, Sachidanandan C, Kamiya N, Fukuda T, Mishina Y, Peterson RT, Bloch KD. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med. 2008 Dec;14(12):1363-9.
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