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].
LDN193189 细胞实验
Cell Line
Concentration
Treated Time
Description
References
IMECs
1 μM
48 h
Inhibits cancer stem cell phenotype, reduces ALDH1+ cell population
Cancer Res. 2013 Jan 15;73(2):1020-30.
HC11 cells
1 μM
48 h
Inhibits cancer stem cell phenotype, reduces ALDH1+ cell population
Cancer Res. 2013 Jan 15;73(2):1020-30.
MC3T3-E1 cells
0.5 μM
3 days
LDN193189 inhibited BMP9-induced activation of the Smad1/5/9 signaling pathway, leading to increased expression of Stat1 and P21, and partially neutralizing the inhibitory effect of BMP9 on SASPs.
Cell Death Discov. 2022 May 6;8(1):254.
bone marrow–derived macrophages (BMDM)
100 nM
24 h
To investigate the effect of BMP signaling inhibition on macrophage activation, results showed that BMP inhibitor combined with β-glucan and LPS increased proinflammatory IL-6 gene expression.
JCI Insight. 2024 Jan 9;9(1):e168517.
human embryonic stem cell-derived dopaminergic neurons
100 nM
11 days
Used for the differentiation of dopaminergic neurons, promoting neuron generation
Used to generate spinal motor neurons as part of the experimental model.
Sci Adv. 2023 Apr 21;9(16):eabq0651.
human pluripotent stem cells (PS cells)
200 nM
2 days
Enhanced differentiation of PS cells into somite-like stage, promoting PAX7-induced myogenesis
Elife. 2019 Nov 11;8:e47970.
MMTV-Myc primary tumor cells
1 μM
48 h
Inhibits cancer stem cell phenotype, reduces ALDH1+ cell population
Cancer Res. 2013 Jan 15;73(2):1020-30.
LDN193189 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Aged mice model
Intraperitoneal injection
3 mg/kg
Once every other day for 12 weeks
LDN193189 reversed the inhibitory effect of BMP9 on Stat1 and downstream senescent genes, and eliminated the improvement of BMP9 on bone mass and trabecular microarchitecture in aged mice.
Cell Death Discov. 2022 May 6;8(1):254.
Mice
Breast cancer bone metastasis model
Osmotic pump
3 mg/kg
Continuous for 7 or 28 days
To investigate the effect of BMP signaling inhibition on breast cancer bone metastasis models, results showed that early BMP inhibition increased bone metastasis growth but reduced lung metastasis.
JCI Insight. 2024 Jan 9;9(1):e168517.
Mice
Ext1 -cKO mouse model
Intraperitoneal injection
10 mg/kg
Every other day for 3 weeks
LDN-193189 significantly reduced the number of hypertrophic chondrocytes and cartilage thickness in Ext1 -cKO mice, and downregulated pSmad1/5/9 expression.
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