1062368-24-4
1062368-24-4 structure
- Name: LDN193189
- Chemical Name: 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline
- CAS Number: 1062368-24-4
- Molecular Formula: C25H22N6
- Molecular Weight: 406.482
- Catalog: Biochemical Inhibitor TGF-beta/Smad signaling pathway inhibitor (TGF-beta/Smad) TGF-beta/Smad inhibitor
- Create Date: 2018-10-22 11:03:40
- Modify Date: 2024-01-03 17:02:54
-
LDN193189 is a BMP signaling inhibitor, inhibiting ALK1, ALK2, ALK3 and ALK6 with IC50s of 0.8, 0.8, 5.3, 16.7 nM, respectively.
| Name | 4-[6-(4-piperazin-1-ylphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline |
|---|---|
| Synonyms |
4-{6-[4-(1-Piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl}quinoline
4-[6-[4-(1-Piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline hydrochloride DM-3189 Quinoline, 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]- UNII-W69H5YQU9O cc-233 S2618_Selleck LDN193189 6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine |
| Description | LDN193189 is a BMP signaling inhibitor, inhibiting ALK1, ALK2, ALK3 and ALK6 with IC50s of 0.8, 0.8, 5.3, 16.7 nM, respectively. |
|---|---|
| Related Catalog | |
| Target |
IC50: 5 nM (ALK2), 30 nM (ALK3)[1] |
| In Vitro | LDN-193189 inhibits BMP4-mediated Smad1, Smad5 and Smad8 activation with greater potency than did dorsomorphin (IC50=5 nM versus 470 nM) while retaining 200-fold selectivity for BMP signaling versus TGF-β signaling (IC50 for TGF-β ≥1,000 nM). LDN-193189 efficiently inhibits transcriptional activity of the BMP type I receptors ALK2 and ALK3 (IC50=5 nM and 30 nM, respectively), with substantially weaker effects on activin and the TGF-β type I receptors ALK4, ALK5 and ALK7 (IC50≥500 nM) and increases selectivity for BMP signaling versus AMP-activated protein kinase, PDGFR and MAPK signaling pathways as compared to the parent compound. LDN-193189 blocks the transcriptional activity induced by either constitutively active ALK2R206H or ALK2Q207D mutant proteins. These findings suggest that LDN-193189 might affect BMP-induced osteoblast differentiation. In fact, LDN-193189 inhibits the induction of alkaline phosphatase activity in C2C12 cells by BMP4 even when administered 12 h after BMP stimulation, indicating sustained BMP signaling activity is needed for osteogenic differentiation[1]. |
| In Vivo | In the first experiment, LDN-193189 (3 mg/kg) is injected intraperitoneally twice a day after tumors became palpable 7 days post-implantation. The growth rates between the control vehicle- and LDN-193189-treated mice are not significantly different after the first 5 weeks, but differences in the growth rates are detected after 6 and 7 weeks post-treatment. In the second experiment, cells are isolated from PCa-118b tumors and injected subcutaneously into SCID mice (1×106 cells per mouse). LDN-193189 or vehicle is applied to mice 5 days post-tumor cell injection before tumors are palpable. The differences in the average growth rates between these two groups, as measured by tumor size, are significant at 6 and 7 weeks post-treatment. The tumor weights also show significant differences at the termination of the study at week 7. The X-ray of the tumors shows that the ectopic bone volume and bone density are reduced in the tumors of LDN-193189-treated group compared to that of controls[2]. Co-incubation of pulmonary arterial smooth muscle cells (PASMCs) from the pulmonary arterial hypertension (PAH) rats with Sildenafil and LDN-193189 completely inhibited the anti-proliferation and up-regulation of the bone morphogenetic protein (BMPR2) and Cx40 expression by the Sildenafil[3]. |
| Kinase Assay | 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 | 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 Admin | 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 |
| Density | 1.3±0.1 g/cm3 |
|---|---|
| Molecular Formula | C25H22N6 |
| Molecular Weight | 406.482 |
| Exact Mass | 406.190582 |
| PSA | 58.35000 |
| LogP | 1.81 |
| Appearance | yellow to orange |
| Index of Refraction | 1.740 |
| Storage condition | ?20°C |
| Water Solubility | H2O: soluble5mg/mL, clear (warmed) |
|
SECTION 1: Identification of the substance/mixture and of the company/undertaking Product identifiers Product name: LDN193189 dihydrochloride REACH No.: A registration number is not available for this substance as the substance or its uses are exempted from registration, the annual tonnage does not require a registration or the registration is envisaged for a later registration deadline.
Relevant identified uses of the substance or mixture and uses advised against Identified uses: Laboratory chemicals, Manufacture of substances SECTION 2: Hazards identification Classification of the substance or mixture Not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008. This substance is not classified as dangerous according to Directive 67/548/EEC. Label elements This substance is not classified as dangerous according to Directive 67/548/EEC. Other hazards - none SECTION 3: Composition/information on ingredients Substances Synonyms: 4-[6-[4-(1-Piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-quinoline dihydrochloride Formula: C25H22N6.2HCl Molecular Weight: 479,40 g/mol No components need to be disclosed according to the applicable regulations. SECTION 4: First aid measures Description of first aid measures no data available Most important symptoms and effects, both acute and delayed The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in section 11 Indication of any immediate medical attention and special treatment needed no data available SECTION 5: Firefighting measures Extinguishing media no data available Special hazards arising from the substance or mixture Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas Advice for firefighters no data available Further information no data available SECTION 6: Accidental release measures Personal precautions, protective equipment and emergency procedures For personal protection see section 8. Environmental precautions no data available Methods and materials for containment and cleaning up no data available Reference to other sections For disposal see section 13. SECTION 7: Handling and storage Precautions for safe handling For precautions see section 2.2. Conditions for safe storage, including any incompatibilities Recommended storage temperature: -20 °C Specific end use(s) A part from the uses mentioned in section 1.2 no other specific uses are stipulated SECTION 8: Exposure controls/personal protection Control parameters Components with workplace control parameters Exposure controls no data available SECTION 9: Physical and chemical properties Information on basic physical and chemical properties a) AppearanceForm: solid b) Odourno data available c) Odour Thresholdno data available d) pHno data available e) Melting point/freezingno data available point f) Initial boiling point and no data available boiling range g) Flash pointno data available h) Evapouration rateno data available i) Flammability (solid, gas) no data available j) Upper/lowerno data available flammability or explosive limits k) Vapour pressureno data available l) Vapour densityno data available m) Relative densityno data available n) Water solubilityno data available o) Partition coefficient: n- no data available octanol/water p) Auto-ignitionno data available temperature q) Decompositionno data available temperature r) Viscosityno data available s) Explosive propertiesno data available t) Oxidizing propertiesno data available Other safety information no data available SECTION 10: Stability and reactivity Reactivity no data available Chemical stability no data available Possibility of hazardous reactions no data available Conditions to avoid no data available Incompatible materials Strong oxidizing agents Hazardous decomposition products In the event of fire: see section 5 SECTION 11: Toxicological information Information on toxicological effects Acute toxicity no data available Skin corrosion/irritation no data available Serious eye damage/eye irritation no data available Respiratory or skin sensitisation no data available Germ cell mutagenicity no data available Carcinogenicity IARC:No component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. Reproductive toxicity no data available Specific target organ toxicity - single exposure no data available Specific target organ toxicity - repeated exposure no data available Aspiration hazard no data available Additional Information RTECS: Not available To the best of our knowledge, the chemical, physical, and toxicological properties have not been thoroughly investigated. SECTION 12: Ecological information Toxicity no data available Persistence and degradability no data available Bioaccumulative potential no data available Mobility in soil no data available Results of PBT and vPvB assessment PBT/vPvB assessment not available as chemical safety assessment not required/not conducted Other adverse effects no data available SECTION 13: Disposal considerations Waste treatment methods no data available SECTION 14: Transport information UN number ADR/RID: -IMDG: -IATA: - UN proper shipping name ADR/RID: Not dangerous goods IMDG: Not dangerous goods IATA:Not dangerous goods Transport hazard class(es) ADR/RID: -IMDG: -IATA: - Packaging group ADR/RID: -IMDG: -IATA: - Environmental hazards ADR/RID: noIMDG Marine pollutant: noIATA: no Special precautions for user no data available SECTION 15: Regulatory information This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006. Safety, health and environmental regulations/legislation specific for the substance or mixture no data available Chemical Safety Assessment For this product a chemical safety assessment was not carried out SECTION 16: Other information |
| HS Code | 29339900 |
|---|
|
~88%
1062368-24-4 |
| Literature: THE GENERAL HOSPITAL CORPORATION; THE BRIGHAM AND WOMEN'S HOSPITAL, INC. Patent: WO2009/114180 A1, 2009 ; Location in patent: Page/Page column 68-69 ; |
| Precursor 1 | |
|---|---|
| DownStream 0 | |