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| 5mg |
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| 10mg |
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| 25mg |
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BRD0705 is a novel, potent, paralog selective and orally bioactive glycogen synthase kinase 3α (GSK3α) inhibitor with an IC50 of 66 nM and a Kd of 4.8 μM. GSK3 is a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target for many diseases. Potential neoplastic worries are lessened by the GSK3-selective substance BRD0705, which inhibits kinase activity without stabilizing -catenin. In AML cells, BRD0705 induces myeloid differentiation and hinders colony formation, but it has no apparent impact on healthy hematopoietic cells. BRD0705 also prolongs survival in AML mouse models and hinders leukemia initiation. These studies show that paralog-selective GSK3α inhibition is feasible and offers a promising therapeutic method for AML.
| Targets |
GSK3α (IC50 = 66 nM); GSK3α (Kd = 4.8 μM); GSK-3β(WT) (IC50 = 515 nM)
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|---|---|
| ln Vitro |
BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 has no effect on healthy hematopoietic cells, but it causes myeloid differentiation and hinders colony formation in AML cells. [1]
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| ln Vivo |
BRD0705 delays leukemia initiation and lengthens survival in AML mouse models.[1]
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| Cell Assay |
After 24 hours of treatment with DMSO or BRD0705 at 20 μM, 30,000 to 50,000 cells are washed in PBS/2%FBS and then cytospun onto poly-L-Lysine coated slides (EMS). The cells are then blocked in 1% BSA/0.05% triton for 1 hour at room temperature, fixed in 4% paraformaldehyde (EMS) for 20 minutes, permeabilized in 0.2% Triton X-100 (RPI) for 30 minutes at 4°C, and incubated for 1 hour at room temperature with primary anti-β-catenin (1/500) and secondary antibody. After each antibody incubation, there are three 5 minute washes. The Yokogawa Spinning Disk Confocal / TIRF system is used to image the slides after mounting them with Prolong (R) Gold Antifade with DAPI. Image-J software is used to analyze representative images from three separate experiments.
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| Animal Protocol |
8-week-old male NSG mice injected with MLL-AF9 AML cells
30 mg/kg Oral gavage; twice daily |
| References |
| Molecular Formula |
C16H12CLNO4S
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|---|---|
| Molecular Weight |
321.42
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| Exact Mass |
321.1841
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| Elemental Analysis |
C, 74.74; H, 7.21; N, 13.07; O, 4.98
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| CAS # |
2056261-41-5
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| Related CAS # |
BRD5648;2056261-42-6;(Rac)-BRD0705;1597440-03-3
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| Appearance |
Solid powder
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| SMILES |
CC[C@@]1(C2=C(NC3=C1C(=O)CC(C3)(C)C)NN=C2)C4=CC=CC=C4
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| InChi Key |
NCKLQXXBRWCYMA-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C20H23N3O/c1-4-20(13-8-6-5-7-9-13)14-12-21-23-18(14)22-15-10-19(2,3)11-16(24)17(15)20/h5-9,12H,4,10-11H2,1-3H3,(H2,21,22,23)/t20-/m0/s1
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| Chemical Name |
(4S)-4-ethyl-7,7-dimethyl-4-phenyl-1,6,8,9-tetrahydropyrazolo[3,4-b]quinolin-5-one
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| Synonyms |
BRD0705; BRD-0705; BRD 0705
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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 |
| 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: 64~300 mg/mL (199.1~933.4 mM)
Ethanol: ~64 mg/mL (~199.1 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (23.33 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 75.0 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. Solubility in Formulation 2: ≥ 7.5 mg/mL (23.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 75.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1112 mL | 15.5560 mL | 31.1119 mL | |
| 5 mM | 0.6222 mL | 3.1112 mL | 6.2224 mL | |
| 10 mM | 0.3111 mL | 1.5556 mL | 3.1112 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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