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G-749 FLT3 inhibitor

Cat.No.S7545

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.
G-749 FLT3 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 521.41

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Quality Control

Batch: Purity: 99.21%
99.21

Solubility

In vitro
Batch:

DMSO : 24 mg/mL (46.02 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 521.41 Formula

C25H25BrN6O2

 Storage (From the date of receipt)
CAS No. 1457983-28-6 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles CN1CCC(CC1)NC2=NC3=C(C(=O)NC=C3Br)C(=N2)NC4=CC=C(C=C4)OC5=CC=CC=C5

Mechanism of Action

Targets/IC50/Ki
FLT3
(Cell-free assay)
0.4 nM
FLT3 (D835Y)
(Cell-free assay)
0.6 nM
Mer
(Cell-free assay)
1 nM
Aurora B
(Cell-free assay)
6 nM
RET
(Cell-free assay)
9 nM
VEGFR1/FLT1
(Cell-free assay)
18 nM
Fms
(Cell-free assay)
19 nM
Axl
(Cell-free assay)
20 nM
Aurora C
(Cell-free assay)
24 nM
FGFR1
(Cell-free assay)
25 nM
FGFR3
(Cell-free assay)
30 nM
VEGFR2/KDR
(Cell-free assay)
39 nM
c-Kit
(Cell-free assay)
142 nM
IGF-1R
(Cell-free assay)
>300 nM
PDGFRα
(Cell-free assay)
>300 nM
PDGFRβ
(Cell-free assay)
>300 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, this compound 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, it shows strong inhibitory activity with IC50 of <10 nM, and thus overcomes drug resistance. In blasts of AML patients, this chemical also exhibits potent antileukemia activity.
Kinase Assay
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.
In vivo
In MV4-11 xenograft mice, G-749 (30 mg/kg p.o.) effectively inhibits the FLT3 pathway and significantly inhibits tumor growth. In an orthogonal model of bone marrow engraftment using Molm-14 cells, this compound (20 mg/kg p.o.) also inhibits tumor growth and increases survival.
References

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