MOA Inhibitor;ATP Competitive

COMMENT G749 is a highly potent FLT3 kinase inhibitor that also has good activity against mutations such as D835Y and ITD/F691L that confer resistance to AC220. It has good oral bioavailability. However, its significant activity on other RTK and kinases that are likely to contribute to toxicity limits its use as a mechanistic tool. The compound should be used at a very low concentration (below 10 nM) together with other, more selective FLT3 inhibitors such as AC220 and potentially inhibitors that control for off-target activity in particular Aurora B (IC50 6 nM), MERTK (IC50 1 nM).  Jun 4 2021 - 11:41am; This is a high-quality reagent but should be recognized as a dual Flt3/MerTK inhibitor. However, there are other compounds, such as Gilteritinib, an FDA-approved Flt3 inhibitor with a similar kinome profile (also potent versus MerTK), that might be preferred due to its advanced status. Many (all?) other Flt3 inhibitors also inhibit members of the TAM family of kinases, including MerTK, so although this compound does not meet probe selectivity criteria, it may be a useful tool in cells known to be dependent upon Flt3 ITD for proliferation. Because MerTK becomes ectopically expressed in many leukemias (doi:10.1172/jci.insight.85630), activity in non-Flt3 mutant cell lines is also anticipated. Jun 18 2021 - 9:51am; The kinase selectivity of this compound is insufficient to make it a good probe, and especially the potent Mer and Aurora B activity are concerning and potentially contribute to the antiproliferative activity of this compound and its in vivo efficacy.  The authors of the source paper themselves acknowledge that “the inhibition of aurora B and Mer in addition to inhibition of activated FLT3 disease pathways may contribute to a significant antileukemic effect.”  In addition, this compound contains a strongly basic amine, coupled with relatively high lipophilicity, and it would be desirable to see secondary pharmacology profiling data to get a sense of potential promiscuity unrelated to kinase activities. The compound is lacking any pharmacokinetics data to allow for a PK/PD relationship assessment. Jul 26 2021 - 12:09pm

DESCRIPTION Denfivontinib (G-749) is a potent, oral active and ATP competitive FLT3 inhibitor, with IC50s of 0.4 nM and 0.6 nM for FLT3 wild type and FLT3-D835Y, respectively. Denfivontinib can be used for the research of agent resistance for acute myeloid leukemia (AML)[1].

PRICE 111

DESCRIPTION G-749 is a novel and potent inhibitor of wild type and mutant Fms-like tyrosine receptor kinase 3 (FLT3) . We matched its chemical structure to the INN 'denfivontinib' that was released in the WHO's proposed INN list 127 (21 July 2022). (GtoPdb)

MOA Inhibitor (Chemical Probes.org)

DESCRIPTION G-749 potently inhibits autophosphorylation of FLT3 with IC50 of ≤8 nM. In leukemia cells, G-749 shows antiproliferative activity by inducing apoptosis. (BOC Sciences Bioactive Compounds)

DESCRIPTION G-749, a new-type FLT3 inhibitor, exhibits effective and sustained inhibition of the FLT3 wild type and mutants. (TargetMol Bioactive Compound Library)