LDN-193189

ALK inhibitor,potent and selective CAS# 1062368-24-4

LDN-193189

Catalog No. BCC3687----Order now to get a substantial discount!

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Chemical structure

LDN-193189

3D structure

Chemical Properties of LDN-193189

Cas No. 1062368-24-4 SDF Download SDF
PubChem ID 25195294 Appearance Powder
Formula C25H22N6 M.Wt 406.48
Type of Compound N/A Storage Desiccate at -20°C
Synonyms DM-3189
Solubility Ethanol : 0.25 mg/mL (0.62 mM; Need ultrasonic and warming);H2O : < 0.1 mg/mL (insoluble);DMSO : < 1 mg/mL (insoluble or slightly soluble);
Chemical Name 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline
SMILES C1CN(CCN1)C2=CC=C(C=C2)C3=CN4C(=C(C=N4)C5=CC=NC6=CC=CC=C56)N=C3
Standard InChIKey CDOVNWNANFFLFJ-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H22N6/c1-2-4-24-22(3-1)21(9-10-27-24)23-16-29-31-17-19(15-28-25(23)31)18-5-7-20(8-6-18)30-13-11-26-12-14-30/h1-10,15-17,26H,11-14H2
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of LDN-193189

DescriptionLDN193189 is a selective inhibitor of BMP signaling for the BMP type I receptors ALK2 and ALK3 with IC50 of 5 nM and 30 nM, respectively.
TargetsALK2ALK3    
IC505 nM30 nM    

Protocol

Kinase Assay [1]
C2C12 cells are seeded into 96-well plates at 2,000 cells per well in DMEM supplemented with 2% FBS. The wells are treated in quadruplicate with BMP ligands and LDN-193189 or vehicle. The cells are collected after 6 d in culture in 50 μL Tris-buffered saline and 1% Triton X-100. The lysates are added to p-nitro-phenylphosphate reagent in 96-well plates for 1 h and then evaluated alkaline phosphatase activity (absorbance at 405 nm). Cell viability are measured and quantity by Cell Titer Aqueous One (absorbance at 490 nm), using replicate wells treated identically to those used for alkaline phosphatase measurements.

Cell Assay [1]
Mouse PASMCs grown are transiently transfected to 50% confluence in six-well plates with 0.3 μg Id1promoter luciferase reporter construct (BRE-Luc) in combination with 0.6 μg of plasmid expressing constitutively active forms of BMP type I receptors (caALK2, caALK3 or caALK6), using Fugene6. To assess activin and TGF-β type I receptor function, PASMCs are transiently transfected with 0.3 μg PAI1 (plasminogen activator inhibitor-1) promoter luciferase reporter construct (CAGA-Luc) in combination with 0.6 μg of plasmid expressing constitutively active forms of type I receptors (caALK4, caALK5 and caALK7). For both reporter plasmids, 0.2 μg of pRL-TKRenilla luciferase are used to control for transfection efficiency. PASMCs are incubated with LDN-193189 (2 nM-32 μM) or vehicle starting 1 h after transfection. Cell extracts are harvested and quantified relative promoter activity by the ratio of firefly to Renilla luciferase activity with the dual luciferase assay kit.

Animal Administration [2][3]
Mice[2] In the first experiment, SCID mice are implanted with MDA-PCa-118b tumors. After 7 days when tumors reached measurable sizes, mice are injected with LDN-193189 (3 mg/kg) or with vehicle intraperitoneally twice a day. Tumor sizes and body weights are measured weekly. Mice are injected with calcein at three days and one day prior to sacrifice. Blood is collected and tumors are weighed. A portion of the tumors are fixed in formaldehyde for micro-computed tomography (microCT), using EVS CT, or further decalcified for bone histomorphometric analysis, using OsteoMeasure Analysis System, or flash frozen for RNA preparation. Osteocalcin in the mouse serum is determined by ELISA. In the second experiment, PCa-118b tumors are first digested with Accumax, and the isolated cells are plated overnight, resuspended in Matrigel in 1:1 ratio, and injected into SCID mice (1×106 cells/mouse) subcutaneously. Mice are treated with LDN-193189 five days post-injection. Rats[3] Male Sprague-Dawley (SD) rats, 8 weeks of age, weighing 200-220 g, are purchased from Nanjing Medical University animal center. Rats are randomly assigned to one of seven experiment groups (n=6 per group). Rats are housed with free access to food and water under a natural 12/12 h day/night cycle. The Monocrotaline is administered (60 mg/kg) to rats by subcutaneous injection into the back region. The animal’s lungs are harvested at 28th day of the study after hemodynamic assessment. The Sildenafil group received daily intragastric administration of Sildenafil after the administration of MCT (60 mg/kg). The LDN-193189 group received daily intragastric administration of Sildenafil (50 mg/kg) and intraperitoneal injection of LDN-193189 (10 mg/kg). In other groups, the same volume saline is given.

References:
[1]. Yu PB, et al. BMP type I receptor inhibition reduces heterotopic [corrected] ossification. Nat Med, 2008, 14(12), 1363-1369. [2]. Lee YC, et al. BMP4 promotes prostate tumor growth in bone through osteogenesis. Cancer Res, 2011, 71(15), 5194-5203. [3]. Yang L, et al. Sildenefil increases connexin 40 in smooth muscle cells through activation of BMP pathways in pulmonary arterial hypertension. Int J Clin Exp Pathol. 2014 Jul 15;7(8):4674-84.

LDN-193189 Dilution Calculator

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Preparing Stock Solutions of LDN-193189

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.4601 mL 12.3007 mL 24.6015 mL 49.2029 mL 61.5036 mL
5 mM 0.492 mL 2.4601 mL 4.9203 mL 9.8406 mL 12.3007 mL
10 mM 0.246 mL 1.2301 mL 2.4601 mL 4.9203 mL 6.1504 mL
50 mM 0.0492 mL 0.246 mL 0.492 mL 0.9841 mL 1.2301 mL
100 mM 0.0246 mL 0.123 mL 0.246 mL 0.492 mL 0.615 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on LDN-193189

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].

References:
[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.

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References on LDN-193189

Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation.[Pubmed:25368322]

J Biol Chem. 2015 Feb 6;290(6):3390-404.

GDF8, or myostatin, is a member of the TGF-beta superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis.

Dorsomorphin and LDN-193189 inhibit BMP-mediated Smad, p38 and Akt signalling in C2C12 cells.[Pubmed:20691279]

Int J Biochem Cell Biol. 2010 Nov;42(11):1802-7.

Bone morphogenetic proteins (BMPs) are key regulators of cell fate decisions during embryogenesis and tissue homeostasis. BMPs signal through a coordinated assembly of two types of transmembrane serine/threonine kinase receptors to induce Smad1/5/8 plus non-Smad pathways, such as MAPK and Akt. The recent discovery of BMP receptor inhibitors opened new avenues to study specific BMP signalling and to delineate this effect from TGF-beta and Activin signalling. Here we present comprehensive and quantitative analyses on both canonical and non-Smad mediated BMP signalling under Dorsomorphin (DM) and LDN-193189 (LDN) treatment conditions. We demonstrate for the first time, that both compounds affect not only the Smad but also the non-Smad signalling pathways induced by either BMP2, BMP6 or GDF5. The activation of p38, ERK1/2 and Akt in C2C12 cells was inhibited by DM and LDN. In addition "off-target" effects on all branches of BMP non-Smad signalling are presented. From this we conclude that the inhibition of BMP receptors by DM and more efficiently by LDN-193189 affects all known BMP induced signalling cascades.

Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells.[Pubmed:25227893]

Int J Cancer. 2015 Mar 1;136(5):E455-69.

Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.

Description

LDN-193189 is a selective BMP signaling inhibitor, inhibits the transcriptional activity of the BMP type I receptors ALK2 and ALK3 with IC50 of 5 nM and 30 nM in C2C12 cells, respectively, exhibits 200-fold selectivity for BMP versus TGF-β.

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