PLX647 (40 mg/kg) was dosed orally 4.25 h before LPS injection. Treatment with PLX647 reduced serum TNF-α levels by 85% compared with the vehicle control. In the same experiment, the positive control dexamethasone (0.5 mg/kg, PO) lowered the TNF-α levels by 96%. Treatment with 40 mg/kg PLX647 also resulted in significant inhibition of IL-6 release (75%), with similar potency to dexamethasone (70%) . In the UUO kidneys, treatment with PLX647 [40 mg/kg twice daily (BID)] resulted in reduction in the levels of F4/80+ macrophages by 77% compared with vehicle [1].
In Vitro
PLX647 was tested against a panel of 400 kinases at a concentration of 1 μM, 35-fold above its FMS enzymatic IC50 and 60-fold above its KIT enzymatic IC50. In addition to FMS and KIT, the activities of only nine kinases were inhibited by more than 50%. PLX647 potently inhibits the growth of FLT3–ITD-expressing MV4-11 cells (IC50 = 0.11 μM) but not OCI-AML5 (IC50 = 1.6 μM), which express wild-type FLT3. PLX647 displayed minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC50 = 5 μM) [1].
Kinase Assay
Cell Assay
Animal Administration
References
[1]. Zhang C, et al. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5689-94.
[2]. Louvet C, et al. Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18895-900.
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