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Purity: ≥98%
G-749 (G749) is a novel and potent FLT3 inhibitor with potential antineoplastic activity. With IC50 values of 0.4 nM, 0.6 nM, and 1 nM, respectively, it inhibits FLT3 (WT), FLT3 (D835Y), and Mer. Both in vitro and in vivo antitumor efficaciousness of G-749 are demonstrated, along with strong anti-proliferative activity. In a number of drug-resistant environments, including patient plasma, FLT3 ligand surge, and stromal protection, G-749 maintained its inhibitory efficacy.With IC50 values of 0.4 nM, 0.6 nM, and 1 nM, respectively, it inhibits FLT3 (WT), FLT3 (D835Y), and Mer. Both in vitro and in vivo antitumor efficaciousness of G-749 are demonstrated, along with strong anti-proliferative activity. In a number of drug-resistant environments, including patient plasma, FLT3 ligand surge, and stromal protection, G-749 maintained its inhibitory efficacy.
| Targets |
FLT3 (IC50 = 0.4 nM); FLT3 (IC50 = 0.6 nM); Mer (IC50 = 1 nM); Aurora B (IC50 = 6 nM); RET (IC50 = 9 nM)
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| ln Vitro |
G-749 can effectively prevent FLT3 autophosphorylation in FLT3-WT-bearing RS4-11 cells, FLT3-ITD-bearing MV4-11, and Molm-14 cells, with an IC50 of less than 8 nM. G-749 induces apoptosis in leukemia cells to demonstrate antiproliferative activity. G-749 demonstrates potent inhibitory activity with an IC50 of less than 10 nM in BaF3 cell lines that stably express FLT3-ITD/N676D, FLT3-ITD/F691L, FLT3-D835Y, or FLT3-D835Y/N676D, thereby surmounting drug resistance. G-749 also shows strong antileukemia activity in blasts from AML patients.[1]
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| ln Vivo |
G-749 (30 mg/kg p.o.) significantly reduces tumor growth and inhibits the FLT3 pathway in MV4-11 xenograft mice. Using Molm-14 cells in an orthogonal model of bone marrow engraftment, G-749 (20 mg/kg p.o.) also reduces tumor growth and improves survival.[1]
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| Enzyme Assay |
The Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) system from Perkin-Elmer is used for activity assays. In summary, 10 ng/mL FLT3 enzyme, a serially diluted G-749, 80 nM of ULight-poly-GT peptide substrate, and varying concentrations of ATP (8.5 µM to 1088 μM) are combined with kinase assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween-20) and added to a 384-well OptiPlate-384 in a volume of 10 μL. After a maximum of one hour of room temperature incubation, 5 μL of 10 mM EDTA is added to halt the kinase reaction. The particular Eu-labeled anti-phosphopeptide antibody is then added in a volume of 5 μL diluted in LANCE Detection Buffer to a final concentration of 2 nM. Assay plates are incubated at 23°C for 30 minutes after that, and the LANCE signal is measured using an EnVision Multilabel Reader. The 320 nm excitation wavelength is used, and the 615 nm donor and 665 nm acceptor emission wavelengths are tracked. GradPad Prism 5 is used to perform nonlinear regression analysis in order to determine the IC50.
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| Cell Assay |
The test inhibitor concentrations are applied to the cells for 72 hours at 37°C after they are seeded at a density of 2 ×104 cells per well. After being produced from HS-5 cell culture for five days under standard culture conditions, the conditioned medium (CM) is centrifuged to remove any remaining debris and is then used right away. At a final concentration of 35%, the CM is added to the entire medium. In coculture experiments, 1 ×104 HS-5 monolayers and 5 ×104 AML blast cells are plated in 24-well plates, which are then cultured for a minimum of 48 hours prior to the inhibitors being exposed. Utilizing an ATPLite assay, cell viability is assessed.
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| Animal Protocol |
MV4-11 xenograft mouse model and Molm-14 orthogonal mouse model
~30 mg/kg p.o. |
| References |
| Molecular Formula |
C25H25BRN6O2
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| Molecular Weight |
521.41
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| Exact Mass |
520.12
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| Elemental Analysis |
C, 57.59; H, 4.83; Br, 15.32; N, 16.12; O, 6.14
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| CAS # |
1457983-28-6
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CN1CCC(CC1)NC2=NC3=C(C(=O)NC=C3Br)C(=N2)NC4=CC=C(C=C4)OC5=CC=CC=C5
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| InChi Key |
SXWMIXPJPNCXQQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H25BrN6O2/c1-32-13-11-17(12-14-32)29-25-30-22-20(26)15-27-24(33)21(22)23(31-25)28-16-7-9-19(10-8-16)34-18-5-3-2-4-6-18/h2-10,15,17H,11-14H2,1H3,(H,27,33)(H2,28,29,30,31)
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| Chemical Name |
8-bromo-2-[(1-methylpiperidin-4-yl)amino]-4-(4-phenoxyanilino)-6H-pyrido[4,3-d]pyrimidin-5-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.79 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 25.0 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: 2.5 mg/mL (4.79 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 ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (4.79 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 | 1.9179 mL | 9.5894 mL | 19.1788 mL | |
| 5 mM | 0.3836 mL | 1.9179 mL | 3.8358 mL | |
| 10 mM | 0.1918 mL | 0.9589 mL | 1.9179 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.
In vivo antitumor activity of G-749 in xenograft and engrafted mouse model. Blood. 2014 Apr 3; 123(14): 2209–2219. |
Potent inhibition of G-749 in AML patient plasma milieu. Blood. 2014 Apr 3;123(14):2209-19. |
Potent inhibition of G-749 against patient blasts harboring FLT3-ITD or FLT3-D835Y. Blood. 2014 Apr 3;123(14):2209-19. |
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