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.
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.
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.
Description
G-749 is an inhibitor of Fms-like tyrosine receptor kinase 3 (FLT3) with IC
50 values ranging from 2.1 to 38.1 nM for wild-type and mutant (constitutively active) FLT3s in Ba/F3 cells expressing recombinant receptors. It also inhibits growth of human leukemia cell lines that express FLT3-ITD mutant kinase (IC
50s = 3.5 and 7.5 nM for MV4-11 and Molm-14 cells, respectively) but has no effect on cells that lack FLT3 expression or that express wild-type FLT3. G-749 reduces tumor growth and increases survival in a dose-dependent manner in MV4-11 and Molm-14 murine leukemia xenograft models. It reduces growth of bone marrow blasts derived from acute myeloid leukemia patients, showing more potent inhibition of blasts expressing the FLT3-ITD mutant receptor.
Uses
G-749 is a potent FLT3 inhibitor. It shows lower potency against other tyrosine kinases.
References
1. lee h k, kim h w, lee i y, et al. g-749, a novel flt3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. blood, 2014, 123(14): 2209-2219.
