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Purity: ≥98%
A-83-01 is an ALK inhibibitor. It was found that A-83-01 inhibited the transcriptional activity induced by TGF-beta type I receptor ALK-5 and that by activin type IB receptor ALK-4 and nodal type I receptor ALK-7, the kinase domains of which are structurally highly related to those of ALK-5. A-83-01 was found to be more potent in the inhibition of ALK5 than a previously described ALK-5 inhibitor, SB-431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta. A-83-01 inhibited the epithelial-to-mesenchymal transition induced by TGF-beta, suggesting that A-83-01 and related molecules may be useful for preventing the progression of advanced cancers.
| Targets |
ALK5: 12 nM (IC50); ALK4: 45 nM (IC50); ALK7: 7.5 nM (IC50)
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| ln Vitro |
A 83-01 is a strong inhibitor of TGF-β type I receptor ALK5 kinase, ALK4 and ALK7. It also weakly suppresses transcription induced by constitutively active ALK-6, ALK-2, ALK-3, and ALK-1. In Mv1Lu cells, it reduces the level of ALK-5-induced transcription with an IC50 of 12 nM. It also blocks transcription induced by ALK4-TD and ALK7-TD, with IC50s of 45 nM and 7.5 nM in R4-2 cells. At concentrations of 0.03–10 μM, A 83-01 effectively counteracts the growth-inhibitory effects of TGF-β, and at 3 μM, it totally eliminates them. HaCaT cells' Smad activation caused by TGF-β is inhibited by A 83-01 (1–10 μM)[1]. A 83-01 (1 μM) does not alter cell proliferation, but it does reduce TGF-β1-induced cell motility, adhesion, and invasion in HM-1 cells[2].
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| ln Vivo |
Mice without body weight or neurobehavioral performance showed a substantial increase in the quarter rate when given an intraperitoneal dose of 83-01 (50, 150, and 500 μg/mouse) [2]. In mice, 83-01 M109 cells administered intraperitoneally at a dose of 0.5 mg/kg had strong antitumor effects [3].
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| Enzyme Assay |
The original constructions of constitutively active forms of ALK-1 through -7 in mammalian expression vectors were described previously. The 9xCAGA-luciferase plasmid contains nine repeats of the CAGA Smad binding element driving luciferase expression. The (BRE)2-luciferase plasmid contains two repeats of the BMP responsive elements of the Id1 promoter cloned upstream of a minimal promoter driving luciferase expression. The 3GC2-luciferase plasmid contains three repeats of a GC-rich sequence derived from the proximal BMP responsive element of the Smad6 promoter. [1]
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| Cell Assay |
Mv1Lu cells were seeded in duplicate at a density of 2.5 × 104 cells/well in 24-well plates. The following day, cells were pretreated for 1 h with 1 µM small molecule inhibitors and then cultured with TGF-β 1 ng/mL) for 24 h, 48 h, or 72 h. Cells were trypsinized and counted with a Coulter counter. To explore whether small molecule inhibitors reduced the growth-inhibitory effects of TGF-β in concentration-dependent fashion, Mv1Lu cells were seeded as above and pretreated for 1 h with various concentrations of small molecule inhibitors. After pretreatment, cells were cultured with TGF-β 1 ng/mL) for 48 h and counted.[1]
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| Animal Protocol |
Female B6C3F1 mice used for the in vivo studies are maintained under specific pathogen-free conditions. To evaluate the effect of A 83-01 on the survival of mice bearing peritoneal dissemination, HM-1 cells (1×106) are injected into the abdominal cavity via the left flank of the mouse. Starting the next day, A 83-01 (150 μg/body) or vehicles (PBS with 0.5% DMSO) are injected into the abdominal cavity three times per week. Mice are euthanized before reaching the moribund state.
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| References |
[1]. Tojo M, et al. The ALK-5 inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-beta. Cancer Sci. 2005 Nov;96(11):791-800.
[2]. Yamamura S, et al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer. 2012 Jan 1;130(1):20-8. [3]. Taniguchi Y, et al. Enhanced antitumor efficacy of folate-linked liposomal Adriamycin with TGF-β type I receptor inhibitor. Cancer Sci. 2010 Oct;101(10):2207-13 |
| Additional Infomation |
Transforming growth factor (TGF)-beta signaling facilitates tumor growth and metastasis in advanced cancer. Use of inhibitors of TGF-beta signaling may thus be a novel strategy for the treatment of patients with such cancer. In this study, we synthesized and characterized a small molecule inhibitor, A-83-01, which is structurally similar to previously reported ALK-5 inhibitors developed by Sawyer et al. (2003) and blocks signaling of type I serine/threonine kinase receptors for cytokines of the TGF-beta superfamily (known as activin receptor-like kinases; ALKs). Using a TGF-beta-responsive reporter construct in mammalian cells, we found that A-83-01 inhibited the transcriptional activity induced by TGF-beta type I receptor ALK-5 and that by activin type IB receptor ALK-4 and nodal type I receptor ALK-7, the kinase domains of which are structurally highly related to those of ALK-5. A-83-01 was found to be more potent in the inhibition of ALK5 than a previously described ALK-5 inhibitor, SB-431542, and also to prevent phosphorylation of Smad2/3 and the growth inhibition induced by TGF-beta. In contrast, A-83-01 had little or no effect on bone morphogenetic protein type I receptors, p38 mitogen-activated protein kinase, or extracellular regulated kinase. Consistent with these findings, A-83-01 inhibited the epithelial-to-mesenchymal transition induced by TGF-beta, suggesting that A-83-01 and related molecules may be useful for preventing the progression of advanced cancers.[1]
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| Molecular Formula |
C25H19N5S
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| Molecular Weight |
421.52
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| Exact Mass |
421.136
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| Elemental Analysis |
C, 71.23; H, 4.54; N, 16.61; S, 7.61
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| CAS # |
909910-43-6
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| Related CAS # |
A 83-01 sodium;2828431-89-4;A 83-01;909910-43-6
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| PubChem CID |
16218924
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.27g/cm3
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| Boiling Point |
590ºC at 760 mmHg
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| Flash Point |
310.6ºC
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| Index of Refraction |
1.706
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| LogP |
5.786
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
31
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| Complexity |
609
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S=C(N1C=C(C2C3C(=CC=CC=3)N=CC=2)C(C2C=CC=C(C)N=2)=N1)NC1C=CC=CC=1
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| InChi Key |
HIJMSZGHKQPPJS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H19N5S/c1-17-8-7-13-23(27-17)24-21(19-14-15-26-22-12-6-5-11-20(19)22)16-30(29-24)25(31)28-18-9-3-2-4-10-18/h2-16H,1H3,(H,28,31)
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| Chemical Name |
3-(6-methylpyridin-2-yl)-N-phenyl-4-(quinolin-4-yl)-1H-pyrazole-1-carbothioamide
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| Synonyms |
A8301; A 8301; 909910-43-6; A 83-01; 3-(6-methylpyridin-2-yl)-N-phenyl-4-(quinolin-4-yl)-1H-pyrazole-1-carbothioamide; A-83-01; A83-01; Stemolecule A83-01; 3-(6-methylpyridin-2-yl)-N-phenyl-4-quinolin-4-ylpyrazole-1-carbothioamide; X3ZNM7QJ2Q; A-8301
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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 is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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 : ~25 mg/mL (~59.31 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: 1.25 mg/mL (2.97 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (2.97 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3724 mL | 11.8618 mL | 23.7237 mL | |
| 5 mM | 0.4745 mL | 2.3724 mL | 4.7447 mL | |
| 10 mM | 0.2372 mL | 1.1862 mL | 2.3724 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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