G749

G749 : ATP competitive inhibitor of FLT3

Structure

Information

  • FLT3
  • Inhibitor, ATP Competitive

In Vitro Validations

Uniprot ID: P36888
Target Class: Protein kinase
Target SubClass: TK
Potency: IC50
Potency Value: 0.4 nM FLT3-WT, 0.6 nM FLT3-D835Y
Potency Assay: TR-FRET Kinase Assay
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Receptor-type tyrosine-protein kinase FLT3, STK1, ...

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 Mer 1 nM , Aurora B 6 nM, RET 9 nM , VEGFR1/FLT1 18 nM, Fms 19 nM , Axl 20 nM , Aurora C 24 nM , FGFR1 25 nM, FGFR3 30 nM, VEGFR2/KDR 39 nM, c-Kit 142 nM
Potency assay (off target): TR-FRET
Probe Selectivity in Vitro:

IGF-1R, PDGFRα, PDGFRβ IC50 > 300 nM

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SERP ratings and comments


SERP Ratings

In Cell Rating

SERP Comments:

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). 

(last updated: 4 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 14 Jun 2021 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 26 Jul 2021 )