PLX647 是一种高度特异性的，具有口服活性的 FMS 和 KIT 双激酶抑制剂，IC50 分别为 28 和 16 nM。PLX647 (1 μM) 在 400 个激酶组中显示出对 FMS 和 KIT 有选择性，但 FLT3 和 KDR 除外 (IC50=91 和 130 nM)。
In vitro, PLX647 potently inhibits proliferation of BCR-FMS cells, with an IC
50
of 92 nM. A corresponding Ba/F3 cell line expressing BCR-KIT is also quite sensitive to PLX647, with an IC
50
of 180 nM. PLX647 also inhibits endogenous FMS and KIT, as demonstrated by inhibition of the ligand-dependent cell lines M-NFS-60 (IC
50
=380 nM) and M-07e (IC
50
=230 nM), which express FMS and KIT, respectively.
PLX647 potently inhibits the growth of FLT3–ITD-expressing MV4-11 cells (IC
50
=110 nM). PLX647 displayed minimal inhibition of the proliferation of Ba/F3 cells expressing BCR–KDR (IC
50
=5 μM). PLX647 inhibits osteoclast differentiation with an IC
50
of 0.17 μM.
PLX647 (40 mg/kg; p.o.; twice daily for 7 days) reduces macrophage accumulation in UUO kidney and blood monocytes.
PLX647 (40 mg/kg; p.o.; male Swiss Webster mice) reduces LPS-induced TNF-α and IL-6 release.
PLX647 (20-80 mg/kg; p.o.; daily or twice daily from 27-41 days) shows effects on collagen-induced arthritis.
PLX647 (30 mg/kg) results in significant inhibition of TRAP5b immunostaining and bone osteolysis. PLX647 (30 mg/kg BID) is able to prevent bone damage by the tumor cells.
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Animal Model:
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Male C57BL/6 mice (mouse unilateral ureter obstruction model)
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Dosage:
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40 mg/kg
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Administration:
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P.o.; twice daily for 7 days
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Result:
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Resulted in reduction in the levels of F4/80+ macrophages by 77%.
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Animal Model:
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7-9 wk old Male DBA/1J mice (Mouse collagen-induced arthritis model)
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Dosage:
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20 mg/kg, 80 mg/kg
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Administration:
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P.o.; daily (20 mg/kg) from 27-41 days, twice daily (80 mg/kg) from 27-41 days
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Result:
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20 mg/kg PLX647 had no initial effect on the development of severe arthritis. However, starting on day 33, no further development of disease severity was recorded, and a 30% inhibition of the macroscopic signs of arthritis was evident in clinical score on day 41. Mice treated with 80 mg/kg BID PLX647 initially shows delayed development of severe arthritic signs. Starting on day 33, the signs of arthritis began to decrease in this treatment group, reaching a maximum reversal of 76% on day 41.
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