FMS/KIT Dual Kinase Inhibitor, PLX647

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-α 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).

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.).

Cell permeable: yes

Primary Target
FMS

Reversible: yes

Secondary Target
KIT

Packaged under inert gas

Toxicity: Standard Handling (A)

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

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

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