Biochem/physiol Actions

Secondary TargetKIT

Reversible: yes

Cell permeable: yes

Primary TargetFMS

General description

A cell-permeable and bio-available azaindolylmethylpyridamine derivative that acts as a potent inhibitor against FMS and KIT (IC₅₀ = 28 and 16 nM, respectively) by targeting the kinases in their inactive DGF-out conformation, while being less effective against Flt3, KDR/VEGFR2, CDC2L6/CDK11/CDK19, NTRK3/TrkC, DDR2, CDK8/cyclin C (IC₅₀ = 91, 130, 350, 620, 700, and 710 nM, respectively) and exhibiting much reduced or little potency toward other kinases in a 400-kinase panel study (IC₅₀ >1 µM). Shown to effectively inhibit cellular FLT3-ITD, FMS, KIT phosphorylations (IC₅₀ from 20 to 250 nM), as well as FLT3-ITD-, FMS-, KIT-dependent proliferations (IC₅₀ from 92 to 380 nM). Exhibits in vivo efficacy in several murine inflammation models (20 to 80 mg/kg b.i.d.; p.o.) and in preventing rat MRMT-1 breast carcinoma bone metastases-caused osteolysis (30 mg/kg b.i.d.; p.o.).

A cell-permeable and bio-available azaindolylmethylpyridamine derivative that acts as a potent inhibitor against FMS and KIT (IC₅₀ = 28 and 16 nM, respectively) by targeting and locking these two PDGF family receptor kinases in their inactive DGF-out conformation, while being less effective against Flt3, KDR/VEGFR2, CDC2L6/CDK11/CDK19, NTRK3/TrkC, DDR2, CDK8/cyclin C (IC₅₀ = 91, 130, 350, 620, 700, and 710 nM, respectively) and exhibiting much reduced or little potency toward other kinases in a 400-kinase panel selectivity study (IC₅₀ >1 µM). Shown to effectively inhibit CSF-1-induced (with RANKL as co-stimulator) osteoclast differentiation (IC₅₀ = 170 nM), cellular FLT3-ITD, FMS, KIT phosphorylations (IC₅₀ ranges from 20 to 250 nM), as well as FLT3-ITD-, FMS-, KIT-dependent proliferations (IC₅₀ ranges from 92 to 380 nM), while being less effective against KDR- or wt FLT3-dependent proliferations (IC₅₀ ranges from 1.6 to 5 µM). Orally available in rats (AUC_0-∞ (h·µg/mL)/C_max (µg/mL) = 6.4/0.63 and 46.35/3.72 post 10 mg/kg and 40 mg/kg oral dosage, respectively) and mice (AUC_0-∞ (h·µg/mL)/C_max (µg/mL) = 8.51/1.67 and 53.3/7.78 post 10 mg/kg and 40 mg/kg oral dosage, respectively) and is reported to exhibit in vivo efficacy in preventing rat MRMT-1 breast carcinoma bone metastases-caused osteolysis (30 mg/kg b.i.d.) as well as in blocking inflammation responses in several murine models, including UUO- (unilateral ureter obstruction) induced kidney inflammation (40 mg/kg b.i.d.), collagen-induced arthritis (20 to 80 mg/kg b.i.d.), LPS-induced serum IL-6 & TNF-A release (single 40 mg/kg oral dose 4.25 h before LPS), and mast cell activation-induced anaphylaxis (single 80 mg/kg oral dose 2 h before antigen stimulation).

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Zhang, C., et al. 2013. Proc. Natl. Acad. Sci. USA110, 5689.

Packaging

Packaged under inert gas

10 mg in Glass bottle

Reconstitution

Following reconstitution, aliquot and freeze (-20°C. Stock solutions are stable for up to 3 months at -20°C.

Warning

Toxicity: Standard Handling (A)