G-749

Catalog No.S7545 Batch:S754503

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Technical Data

Formula

C25H25BrN6O2
Molecular Weight 521.41 CAS No. 1457983-28-6
Solubility (25°C)* In vitro DMSO 27 mg/mL (51.78 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description G-749 is a novel and potent FLT3 inhibitor with IC50 of 0.4 nM, 0.6 nM and 1 nM for FLT3 (WT), FLT3 (D835Y), and Mer, respectively, showing lower potency against other tyrosine kinases.
Targets
FLT3 [1]
(Cell-free assay)		 FLT3 (D835Y) [1]
(Cell-free assay)		 Mer [1]
(Cell-free assay)		 Aurora B [1]
(Cell-free assay)		 RET [1]
(Cell-free assay)		 View More
0.4 nM 0.6 nM 1 nM 6 nM 9 nM
In vitro In FLT3-WT-bearing RS4-11 cells and FLT3-ITD-harboring MV4-11 and Molm-14 cells, G-749 potently inhibits autophosphorylation of FLT3 with IC50 of ≤8 nM. In leukemia cells, G-749 shows antiproliferative activity by inducing apoptosis. In BaF3 cell lines that stably express FLT3-ITD/N676D, FLT3-ITD/F691L, FLT3-D835Y, or FLT3-D835Y/N676D, G-749 shows strong inhibitory activity with IC50 of <10 nM, and thus overcomes drug resistance. In blasts of AML patients, G-749 also exhibits potent antileukemia activity. [1]
In vivo In MV4-11 xenograft mice, G-749 (30 mg/kg p.o.) effectively inhibits the FLT3 pathway and significant inhibits tumor growth. In an orthogonal model of bone marrow engraftment using Molm-14 cells, G-749 (20 mg/kg p.o.) also inhibits tumor growth and increases survival. [1]

Protocol (from reference)

Kinase Assay:

[1]
  • Kinase assay

    Activity assays are conducted using Lance Ultra time-resolved fluorescence resonance energy transfer (TR-FRET) technology from Perkin-Elmer. Briefly, 10 ng/mL FLT3 enzyme, a serial diluted G-749, 80 nM substrate of ULight-poly-GT peptide and variable amounts of ATP (8.5 µM to 1088 μM) are mixed in kinase assay buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT and 0.01% Tween-20) and are added to a 384-well OptiPlate-384 in a volume of 10 μL. Kinase reactions are incubated at room temperature for up to 1 h and then stopped by the addition of 5 μL of 10 mM EDTA. A volume of 5 μL of the specific Eu-labeled-anti-phosphopeptide antibody diluted in LANCE Detection Buffer is then added to a final concentration of 2 nM. After 30-minute incubation, assay plates are incubated at 23°C and the LANCE signal is measured on an EnVision Multilabel Reader. Excitation wavelength is set at 320 nm and emission monitored at 615 nm (donor) and 665 nm (acceptor). The IC50 is calculated using nonlinear regression analysis analysis by GradPad Prism 5.
Cell Assay:

[1]
  • Cell lines

    MV4-11, RS4-11, K562, HEL, and Molm-14 cells

  • Concentrations

    ~1 μM

  • Incubation Time

    72 hours

  • Method

    Cells are seeded at a density of 2 ×104 cells per well and treated with the indicated concentrations of test inhibitor for 72 hours at 37℃. The conditioned medium (CM) is prepared from HS-5 cell culture for 5 days under routine culture conditions, clarified by centrifugation, and used immediately. The CM is added to complete medium at a final concentration of 35%. In coculture experiments, 5 ×104 AML blast cells are plated in 24-well plates containing 1 ×104 HS-5 monolayers and then cultured for at least 48 hours before the exposure of inhibitors. Cell viability is determined by an ATPLite assay.
Animal Study:

[1]
  • Animal Models

    MV4-11 xenograft mouse model and Molm-14 orthogonal mouse model

  • Dosages

    ~30 mg/kg

  • Administration

    p.o.

Selleck's G-749 has been cited by 1 publication

G-749 Promotes Receptor Tyrosine Kinase TYRO3 Degradation and Induces Apoptosis in Both Colon Cancer Cell Lines and Xenograft Mouse Models [ Front Pharmacol, 2021, 12:730241] PubMed: 34721022

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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