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| Targets |
AZ-12799734 targets TGF-β type I receptors, specifically ALK1 (Kd = 7.1 µM), ALK2 (Kd = 6.2 µM), ALK3 (Kd = 40 µM), ALK4 (Kd = 1 µM), ALK5 (Kd = 0.74 µM), and ALK6 (Kd = 0.017 µM). The compound is a potent inhibitor of ALK5 (TGFBR1), which is the primary receptor for TGF-β signaling. AZ-12799734 inhibits ALK5-dependent Smad2 nuclear translocation upon TGF-β1 stimulation with IC50 = 17 nM in MDA-MB-468 cells. The compound also inhibits ALK1/2/3/6-mediated Smad1 phosphorylation and ALK4/5/7-mediated Smad2 phosphorylation (10 µM; NIH3T3 expressing respective constitutively active receptors). As a pan inhibitor of BMP and TGFβ signaling, AZ-12799734 blocks both the SMAD-dependent and potentially SMAD-independent pathways downstream of these receptors. This multi-target profile makes the compound useful for studying the complex signaling networks involving TGF-β and BMP pathways.
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| ln Vitro |
Ligand-activated SMAD3/4 transcription is inhibited by AZ12799734 [1]. AZ12799734 (10 nM; 24 hours) prevents SMAD1 and SMAD2 from being phosphorylated [1]. In HaCaT epithelial cells, AZ12799734 (500 nM; 36 h) suppresses TGFβ-induced migration [1].
In vitro, AZ-12799734 demonstrates potent inhibition of TGF-β and BMP signaling. The compound inhibits ligand-activated SMAD3/4 transcription with IC50 = 47 nM. AZ-12799734 (10 nM; 24 hours) prevents SMAD1 and SMAD2 from being phosphorylated, indicating inhibition of both BMP and TGF-β signaling pathways. The compound inhibits receptor-mediated phosphorylation of SMAD1 by ALK1, BMPR1A, and BMPR1B, and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ-12799734 inhibits TGFB-induced migration in HaCaT cells, demonstrating functional inhibition of TGF-β-mediated cellular responses. The compound's pan-inhibitory activity against both BMP and TGF-β pathways makes it a valuable tool for studying the interplay between these two important signaling systems. These in vitro activities support the compound's use in research on fibrosis, cancer, and other diseases involving dysregulated TGF-β and BMP signaling. |
| ln Vivo |
Rats are exposed to AZ12799734 (0-400 mg/kg/day; oral; 3-7 days) which causes histopathological damage to the heart valves [2]. With an in vitro IC50 of 0.01885 μM, AZ12799734 (50 mg/kg; oral; once) showed total and free pharmacokinetic (PK) levels in nude mice [1].
In vivo, AZ-12799734 is orally active, making it suitable for convenient administration in animal studies. However, toxicity has been observed at high doses: oral administration in rats results in heart valve lesions (200 mg/kg/day for 5 days) and physeal dysplasia (400 mg/kg/day for 6 days), consistent with the critical role of ALK5 in maintaining the integrity of heart valve and physis. These findings highlight the importance of ALK5 signaling in maintaining tissue integrity and the potential toxicity associated with prolonged inhibition of this pathway. The compound's in vivo effects are consistent with the known biology of TGF-β signaling, where ALK5 plays essential roles in development, tissue homeostasis, and disease. The compound's oral activity and documented toxicity profile make it useful for studying TGF-β biology in vivo, but careful dose selection is required. |
| Enzyme Assay |
In vitro kinase assays are used to characterize AZ-12799734's inhibitory activity against TGF-β type I receptors. The compound is tested against a panel of ALK receptors using biochemical kinase assays. Kd values are determined: ALK1 (7.1 µM), ALK2 (6.2 µM), ALK3 (40 µM), ALK4 (1 µM), ALK5 (0.74 µM), and ALK6 (0.017 µM). Cellular assays measure inhibition of SMAD phosphorylation: AZ-12799734 (10 nM; 24 hours) prevents SMAD1 and SMAD2 phosphorylation. The compound inhibits ALK5-dependent Smad2 nuclear translocation upon TGF-β1 stimulation with IC50 = 17 nM in MDA-MB-468 cells. These assays demonstrate the compound's potency and mechanism of action as a pan-TGF-β/BMP inhibitor. Selectivity for different ALK receptors is assessed by comparing inhibition across the receptor panel.
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| Cell Assay |
Western Blot Analysis [1]
Cell Types: HaCaT cells and NIH3T3 cells Tested Concentrations: 10 nM Incubation Duration: 10 days (HaCaT) or 24 hrs (hours) (NIH3T3) Experimental Results: Blocks TGFβ-mediated induction of SMAD2 phosphorylation. Inhibits the phosphorylation of SMAD1 and SMAD2. Cell migration assay[1] Cell Types: HaCaT epithelial cells Tested Concentrations: 500 nM Incubation Duration: 36 hrs (hours) Experimental Results: A dose-dependent decrease in TGFβ-induced migration was observed. Cell-based assays for AZ-12799734 are conducted in various cell lines including MDA-MB-468 (breast cancer), HaCaT (keratinocytes), and NIH3T3 cells expressing constitutively active receptors. Cells are treated with AZ-12799734 at various concentrations (e.g., 10 nM, 24 hours). SMAD phosphorylation is assessed by Western blot using phospho-specific antibodies against SMAD1, SMAD2, and SMAD3. SMAD nuclear translocation is assessed by immunofluorescence or subcellular fractionation. TGFB-induced migration is assessed using Transwell or wound healing assays in HaCaT cells. Gene expression changes (e.g., SMAD target genes) are measured by qPCR. These cell-based assays characterize the compound's effects on TGF-β and BMP signaling and its functional consequences. |
| Animal Protocol |
Animal/Disease Models: Tenweeks old female HsdHan:WIST rats [2]
Doses: 200 and 400 mg/kg/day Route of Administration: po (po (oral gavage)) 3-7 days Experimental Results: Heart valve bleeding was evident under low magnification and normal structure Parts of the lobules are replaced by hemorrhage. The size and number of valvular interstitial cells increase, the cytoplasm increases, the nuclei become enlarged, round, and undergo mitosis frequently. Animal/Disease Models: Female balb/c (Bagg ALBino) mouse [1] Doses: 50 mg/kg Route of Administration: Oral (pharmacokinetic/PK/PK analysis) Experimental Results: Total pharmacokinetic/PK/PK (PK) levels and free PK levels over time pharmacokinetic/PK/PK (PK) levels exceed in vitro IC50 of 0.01885 μM. In vivo animal experiments with AZ-12799734 have been conducted in rats to assess toxicity. Oral administration of AZ-12799734 at 200 mg/kg/day for 5 days results in heart valve lesions, and at 400 mg/kg/day for 6 days results in physeal dysplasia. These findings are consistent with the critical role of ALK5 in maintaining the integrity of heart valve and physis. For efficacy studies, typical designs would involve administration of AZ-12799734 in disease models (e.g., fibrosis, cancer) at doses below the toxic threshold. Route of administration would be oral (p.o.) due to the compound's oral activity. Treatment duration and frequency would depend on the specific model and endpoints. Researchers should carefully select doses to achieve target inhibition while minimizing toxicity. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of AZ-12799734 include oral activity, indicating sufficient oral bioavailability. Specific pharmacokinetic parameters such as half-life, Cmax, Tmax, AUC, volume of distribution, and clearance have not been extensively reported. The compound has molecular weight 370.43 and molecular formula C18H18N4O3S. It is soluble in DMSO and other organic solvents. Storage: powder at -20°C for 3 years, in solvent at -80°C for 1 year. The compound's physicochemical properties suggest it may have suitable characteristics for oral absorption. However, empirical pharmacokinetic data would be needed for detailed characterization and dose optimization. The toxicity observed at high doses (200-400 mg/kg/day) in rats indicates that the compound reaches systemic circulation at these doses.
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| Toxicity/Toxicokinetics |
Toxicology studies in rats have demonstrated that AZ-12799734 causes heart valve lesions at 200 mg/kg/day for 5 days and physeal dysplasia at 400 mg/kg/day for 6 days upon oral administration. These findings are consistent with the known role of ALK5 in maintaining the integrity of heart valve and physis, highlighting the importance of TGF-β signaling in tissue homeostasis. These toxicities are mechanism-based and reflect the critical physiological roles of ALK5. Lower doses may be tolerated and could be used for efficacy studies. Comprehensive toxicology studies (genotoxicity, reproductive toxicity, etc.) have not been extensively reported. The compound is for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling AZ-12799734.
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| References | |
| Additional Infomation |
AZ-12799734 has CAS number 1117684-36-2, molecular formula C18H18N4O3S, and molecular weight 370.43. It is a selective, orally active inhibitor of TGF-β type I receptors (ALK1/2/3/4/5/6) with Kd values: ALK1 (7.1 µM), ALK2 (6.2 µM), ALK3 (40 µM), ALK4 (1 µM), ALK5 (0.74 µM), ALK6 (0.017 µM). The compound functions as a pan inhibitor of BMP and TGFβ signaling pathways, inhibiting ligand-activated SMAD3/4 transcription with IC50 = 47 nM. AZ-12799734 (10 nM; 24 hours) prevents SMAD1 and SMAD2 phosphorylation. The compound inhibits TGFB-induced migration in HaCaT cells. Oral administration in rats causes heart valve lesions (200 mg/kg/day for 5 days) and physeal dysplasia (400 mg/kg/day for 6 days). Synonyms: AZ 12799734, AZ-12799734. Purity: ≥98% (HPLC). Not approved for clinical use; for research purposes only. The compound is a valuable tool for studying TGF-β and BMP signaling in fibrosis, oncology, and other diseases.
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| Molecular Formula |
C18H18N4O3S
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| Molecular Weight |
370.425522327423
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| Exact Mass |
370.109
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| CAS # |
1117684-36-2
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| PubChem CID |
25192277
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
554.0±60.0 °C at 760 mmHg
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| Flash Point |
288.9±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.641
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| LogP |
3.91
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
545
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
UEOZXMAOIHDDQE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18N4O3S/c1-12-3-8-17(13(2)21-12)25-15-9-10-20-18(11-15)22-14-4-6-16(7-5-14)26(19,23)24/h3-11H,1-2H3,(H,20,22)(H2,19,23,24)
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| Chemical Name |
4-[[4-(2,6-dimethylpyridin-3-yl)oxypyridin-2-yl]amino]benzenesulfonamide
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
DMSO : ~125 mg/mL (~337.45 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 | 2.6996 mL | 13.4978 mL | 26.9957 mL | |
| 5 mM | 0.5399 mL | 2.6996 mL | 5.3991 mL | |
| 10 mM | 0.2700 mL | 1.3498 mL | 2.6996 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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