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Purity: ≥98%
BAY-826 is a novel, highly potent, selective and orally available small molecule TIE-2 inhibitor with Kd of 1.6 nM, respectively. In syngeneic mouse glioma models, it enhances tumor control. Angiopoietin-1- or Na3 VO4-induced TIE-2 phosphorylation in glioma cells or lung extracts from BAY-826-treated mice is suppressed, indicating that BAY-826 inhibits TIE-2 phosphorylation both in vitro and in vivo. After receiving a single agent, two out of the four models (SMA-497 and SMA-540) showed a tendency toward longer survival, and one model (SMA-560) showed a significant survival benefit. One model (SMA-497) did not respond well to co-treatment with BAY-826 and radiation, but another model (SMA-560) showed synergistic survival prolongation. Both increased leukocyte infiltration and decreased vessel densities were noted; however, since these effects were also seen with single treatment modalities, it is possible that these processes are independent. These findings show that in highly vascularized tumors like glioblastoma, TIE-2 inhibition may enhance tumor response to therapy. In cases of glioblastoma, targeting the vascular endothelial growth factor signaling axis invariably results in tumor recurrence and an increasingly aggressive phenotype. As a result, additional angiogenic signaling pathways, such as the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have been identified as potential therapeutic targets.
| Targets |
Tie2 (Kd = 1.6 nM)
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|---|---|
| ln Vitro |
BAY-826 is a selective and potent inhibitor of TIE-2 (dissociation constant = 1.6 nM). It binds similarly highly to only 4 out of 456 tested kinases (dissociation constant = 0.9, 0.4, 1.3, and 5.9 nM), which are TIE-1, DDR1, DDR2, and Serine/threonine-protein kinase 10 (LOK).With an EC50 of roughly 1.3 nM for the inhibition of TIE-2 autophosphorylation in human umbilical vein endothelial cells, the high biochemical affinity for TIE-2 translates into very strong cellular mechanistic activity. Using all four mouse glioma cell lines, the acute growth inhibitory and anti-clonogenic effects of the TIE-2 inhibitor BAY-826 are evaluated. The effects of BAY-826 on VEGF-stimulated proliferation of HUVEC are limited to μM concentrations, and it exhibits high selectivity against other angiogenic kinases such as VEGFR, fibroblast growth factor receptor (FGFR), or platelet-derived growth factor receptor (PDGFR).
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| ln Vivo |
BAY-826 (oral gavage; 25 mg/kg,50 mg/kg,100 mg/k) inhibits TIE-2 autophosphorylation induced by ANG-1 in the murine lungs of female CB17/scid mice with a strong potency[1]. In mouse models of syngeneic gliomas, BAY-826 enhances tumor control. In one model (SMA-497), co-treatment with BAY-826 and radiation is ineffective; however, in another model (SMA-560), it has a synergistic effect of prolonging cell survival. In highly vascularized tumors like glioblastoma, TIE- 2 inhibition may enhance the tumor response to treatment[1].
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| Cell Assay |
In mouse models of syngeneic gliomas, BAY-826 enhances tumor control. In one model (SMA-497), co-treatment with BAY-826 and radiation is ineffective; however, in another model (SMA-560), it has a synergistic effect of prolonging cell survival. In highly vascularized tumors like glioblastoma, TIE- 2 inhibition may enhance the tumor response to treatment[1].Glioma cells from SMA-497, SMA-540, SMA-560, and GL-261 in mice are utilized.Typically, the cells are grown as adherent monolayers in Dulbecco's modified Eagle medium, which is enhanced with 2 mM glutamine and 10% heat-inactivated fetal calf serum. In a coradiation source, cells receive radiation at 1, 3, and 9 Gy. The cells are pre-incubated for 10 minutes at 37°C with either 1μM BAY-826 or 0.1% DMSO as the control. For 20 minutes, 400 ng/mL COMP-ANG-1 or 4 mM Na3VO4 are used to induce TIE-2 autophosphorylation in the presence of either 0.1% DMSO or 1 μM BAY-826[1].
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| Animal Protocol |
A burr hole is drilled into the skull 2 mm lateral to the bregma after anesthesia. A Hamilton syringe's needle is inserted three millimeters below the surface. A single cell suspension in PBS, containing 2 μL, is gradually injected into the right striatum. 5×10 3 SMA glioma cells are implanted in female and male VM/Dk mice (house husbandry), while 2×104 GL-261 cells are implanted in female C57Bl/6 mice (Charles River) (n = 10 per group). The mice used are heavier than twenty grams. Systemic treatment with BAY-826 is administered orally at a dose of 100 mg/kg body weight per day, orally with a solvent mixture of 10% ethanol, 40% sorbitol, and 50% water, respectively[1].
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| References | |
| Additional Infomation |
BAY-826 is a secondary carboxamide resulting from the formal condensation of the carboxy group of 3-cyano-5-(pentafluoro-lambda(6)-sulfanyl)benzoic acid with the amino group of 2,4-dimethyl-5-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]aniline. It is a potent TIE-2 inhibitor (Kd = 1.6 nM) which displays in vivo efficacy in some murine glioma models. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a member of pyridines, an imidazopyrazole, a member of benzamides, a secondary carboxamide, a nitrile, an organofluorine compound and an organosulfur compound.
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| Molecular Formula |
C26H19F5N6OS
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|---|---|
| Molecular Weight |
558.525680780411
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| Exact Mass |
558.53
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| Elemental Analysis |
C, 55.91; H, 3.43; F, 17.01; N, 15.05; O, 2.86; S, 5.74
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| CAS # |
1448316-08-2
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| Related CAS # |
1448316-08-2
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| PubChem CID |
71623052
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| Appearance |
White to yellow solid powder
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| LogP |
6.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
39
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| Complexity |
991
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MPASHPJAIUOWCK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H19F5N6OS/c1-16-8-17(2)24(36-6-7-37-25(36)13-23(35-37)19-4-3-5-33-15-19)12-22(16)34-26(38)20-9-18(14-32)10-21(11-20)39(27,28,29,30)31/h3-13,15H,1-2H3,(H,34,38)
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| Chemical Name |
3-cyano-N-[2,4-dimethyl-5-(6-pyridin-3-ylimidazo[1,2-b]pyrazol-1-yl)phenyl]-5-(pentafluoro-lambda6-sulfanyl)benzamide
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| Synonyms |
BAY826; BAY 826; BAY-826
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| HS Tariff Code |
2934.99.03.00
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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: ~100 mg/mL (~179.0 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (1.79 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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. Solubility in Formulation 2: ≥ 1 mg/mL (1.79 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 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. View More
Solubility in Formulation 3: ≥ 1 mg/mL (1.79 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 | 1.7904 mL | 8.9521 mL | 17.9041 mL | |
| 5 mM | 0.3581 mL | 1.7904 mL | 3.5808 mL | |
| 10 mM | 0.1790 mL | 0.8952 mL | 1.7904 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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