LDN193189

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Chemical Structure| 1062368-24-4 同义名 : DM-3189
CAS号 : 1062368-24-4
货号 : A125436
分子式 : C25H22N6
纯度 : 99%+
分子量 : 406.482
MDL号 : MFCD17392570
存储条件：

Pure form Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 9 mg/mL(22.14 mM)，配合低频超声，水浴加热至45℃，并调节pH至2，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

PO 0.5% CMC-Na 38 mg/mL suspension

生物活性
靶点

  • ALK1

    ALK1, IC50:0.8 nM

  • ALK2

    ALK2, IC50:0.8 nM

  • ALK6

    ALK6, IC50:16.7 nM

  • ALK3

    ALK3, IC50:5.3 nM
描述 BMPs (Bone morphogenetic proteins) represent the largest subgroup in the TGFβ family of extracellular ligands. Their signaling transduction requires the interaction with the type I and type II transmembrane receptor kinase. Type I receptors, such as ALK1/ACVRL1, ALK2/ACVR1, ALK3/BMPR1A and ALK6/BMPR1B all participate in BMP signalling and phosphorylate SMAD1/5/ 8 phosphorylate SMAD family transcription factors. Dysregulation of this pathway links to many disease conditions, for example, fibrodysplasia ossificans progressive[1]. LDN-193189 is a selective inhibitor of BMP type I receptors with IC50 values of 5 nM and 30 nM for ALK2 and ALK3 (measured by p-Smad1/5/8 in PASMCs), respectively, with substantially weaker effects on ALK4, ALK5 and ALK7 (IC50≥500 nM). PASMCs treated with LDN-193189 on concentration at 2 - 250 nM showed dose-dependent inhibition on p-Smad1/5/8 induced by BMP4 (10 ng/ml), while retaining 200-fold selectivity for BMP signaling versus TGF-β signaling (IC50≥1000 nM). Even LDN-193189 can block the transcriptional activity induced by either constitutively active ALK2R206H or ALK2Q207D mutant proteins. Intraperitoneal injection with LDN-193189 on dose of 3 mg/kg, every 12 h, resulted in a reduction in ectopic ossification and functional impairment in ALK2Q207D mutant mice[2]. Use of LDN-193189 combined with different small molecular led to the effective generation from ESCs of paraxial mesodermal progeny, and to their further differentiation in vitro through sclerotome specification into growth plate-like chondrocytes[3]. Inhibition of BMP signaling by LDN-193189 can inhibit endothelial cell differentiation in the ventral blood island[4].
作用机制 LDN-193189 targets to the ATP-binding pocket located within the intracellular kinase domain of the receptors[1].
细胞研究
细胞系 浓度 检测类型 检测时间 活性说明 数据源
A549 0.5-16 μM Growth Inhibition Assay inhibits cell growth in a dose-dependent manner 24778011
BEAS-2B 0.5-16 μM Growth Inhibition Assay inhibits cell growth in a dose-dependent manner 24778011
Bx-PC3 5-500 nM Growth Inhibition Assay 48 h inhibits cell growth in a dose-dependent manner 23969729
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.46mL

0.49mL

0.25mL

12.30mL

2.46mL

1.23mL

24.60mL

4.92mL

2.46mL
参考文献

[1]Williams E, Bullock AN, et al. Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2. Bone. 2018 Apr;109:251-258.

[2]Yu PB, Deng DY, et al. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med. 2008 Dec;14(12):1363-9.

[3]Zhao J, Li S, et al. Small molecule-directed specification of sclerotome-like chondroprogenitors and induction of a somitic chondrogenesis program from embryonic stem cells. Development. 2014 Oct;141(20):3848-58.

[4]Myers CT, Krieg PA, et al. BMP-mediated specification of the erythroid lineage suppresses endothelial development in blood island precursors. Blood. 2013 Dec 5;122(24):3929-39.

[5]Derwall M, Malhotra R, et al. Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis. Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):613-22.

[6]Inubushi T, Nozawa S, et al. Aberrant perichondrial BMP signaling mediates multiple osteochondromagenesis in mice. JCI Insight. 2017 Aug 3;2(15). pii: 90049.

[7]Carvalho D, Taylor KR, et al. ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Commun Biol. 2019 May 9;2:156.

[8]Cuny GD, Yu PB, et al. Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4388-92.