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LDN193189 3HCl (LDN-193189; DM-3189), the trihydrochloride salt of LDN193189, is a highly potent and selective inhibitor of the BMP (bone morphogenetic protein) signaling pathway with potential anticancer activity. LDN-193189 also exhibits inhibitory effects on associated vascular inflammation, osteogenic activity, and calcification. It inhibits the transcriptional activity of the BMP type I receptor kinases such as ALK2 (activin receptor-like kinase-2) and ALK3 with IC50 of 5 nM and 30 nM in C2C12 cells, respectively.
| Targets |
ACVR1 (IC50 = 5 nM); BMPR1A (IC50 = 30 nM); ALK2 (IC50 = 5 nM), ALK3 (IC50 = 30 nM)[1]
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|---|---|
| ln Vitro |
LDN193189 is 200 times more selective for BMP signals than TGF-β signals (IC50, for TGF-β≥1000 nM)[1]. It also demonstrates comparable efficacy to the parent compound LDN193189 in inhibiting the solution activity of BMP-type I receptors ALK2 and ALK3 (IC50=5 nM, 30 nM) and TGF-β-type I receptors ALK4, ALK5, and ALK7 (IC50≥500 nM). The polar activity of the constitutively active ALK2R206H or ALK2Q207D mutant proteins can be filled. Even 12 hours after BMP stimulation, LDN193189 inhibits BMP4-induced alkaline phosphatase activity in C2C12 cells [1].
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| ln Vivo |
LDN193189 (tetrahydrochloride) (ip; 3 mg/kg; twice daily) There was no significant difference in the growth rate of the head model and the LDN193189-treated model after the first 5 weeks, and after 6 and 7 weeks of treatment A significant difference in tumor size was found after 6 and 7 weeks of treatment with LDN193189 (subcutaneous injection; 5 days), as well as a significant difference in tumor weight at the end of the study at week 7 [2]. LDN193189 lowers ectopic bone volume LDN193189 conjugated with UK-92480 totally suppresses bone morphogenesis (BMPR2) and the anti-proliferation and up-regulated expression of Cx40 [3].
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| Enzyme Assay |
Alkaline phosphatase activity[1]
We seeded C2C12 cells into 96-well plates at 2,000 cells per well in DMEM supplemented with 2% FBS. We treated the wells in quadruplicate with BMP ligands and LDN-193189 or vehicle. We collected the cells after 6 d in culture in 50 μl Tris-buffered saline and 1% Triton X-100. We added the lysates to p-nitro-phenylphosphate reagent in 96-well plates for 1 h and then evaluated alkaline phosphatase activity (absorbance at 405 nm). We measured cell viability and quantity by Cell Titer Aqueous One (absorbance at 490 nm), using replicate wells treated identically to those used for alkaline phosphatase measurements.
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| Cell Assay |
Immunoblot analysis of Smad1, Smad5 and Smad8 phosphorylation[1]
We mechanically homogenized cell extracts in SDS-lysis buffer (62.5 mM Tris-HCl (pH 6.8), 2% SDS, 10% glycerol, 50 mM dithiothreitol and 0.01% bromophenol blue), separated the proteins by SDS-PAGE, immunoblotted with polyclonal antibodies specific for phosphorylated Smad1, Smad5 and Smad8, phosphorylated Smad2 or rabbit monoclonal antibodies specific for Smad1 or Smad2 , and visualized the immunoreactive proteins with ECL Plus.[1]
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| Animal Protocol |
Mice[3] 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, 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.
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| References |
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| Molecular Formula |
C25H26CL4N6
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|---|---|
| Molecular Weight |
552.326140880585
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| Exact Mass |
552.094
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| CAS # |
2310134-98-4
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| Related CAS # |
LDN193189;1062368-24-4;LDN-193189 dihydrochloride;1435934-00-1
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| PubChem CID |
66576997
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| Appearance |
Light yellow to yellow solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
35
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| Complexity |
587
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.Cl.Cl.Cl.N1(C2C=CC(C3C=NC4=C(C=NN4C=3)C3C=CN=C4C=CC=CC=34)=CC=2)CCNCC1
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| InChi Key |
NYHXPFHFIMRKDS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H22N6.4ClH/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;4*1H
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| Chemical Name |
4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline;tetrahydrochloride
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~33.33 mg/mL (~60.34 mM)
DMSO : ~4.17 mg/mL (~7.55 mM) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8105 mL | 9.0526 mL | 18.1051 mL | |
| 5 mM | 0.3621 mL | 1.8105 mL | 3.6210 mL | |
| 10 mM | 0.1811 mL | 0.9053 mL | 1.8105 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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