It is found that macrophage colony-stimulating factor is important for the differentiation of osteoclasts, thus facilitating it to participate into the development of osteolysis in bone metastatic lesions. Ki20227 is an inhibitor of c-fms tyrosine kinase with IC50 values of 2nM, also showed inhibition against VEGFR2 with IC50 value of 12nM (measured by kinase activity). In cellular study, Ki20227 (>3nM) showed dose-dependent inhibition of M-CSF-dependent c-Fms phosphorylation in RAW264.7 cells cultured in medium supplemented with 0.1% FCS. Also it showed inhibitory activity against M-CSF-dependent and VEGF-dependent cell growth in M-NFS-60 (10-100nM) and HUVEC cells (300-3000nM). As macrophage colony-stimulating factor was important in osteolysis, inhibition of c-Fms kinase by Ki20227 at concentration of 100nM suppressed the development of TRAP-positive osteoclast-like cell formation. Oral administration of 50 mg/kg of Ki20227 daily for 20 days could markedly decrease the osteolytic lesion areas which caused by metastasizing A375 cells in nude rats. Once daily oral treatment with Ki20227 at 20 mg/kg for 28 days significantly reduced the TRAP-positive osteoclastic cells on the bone surface in the primary spongiosa in ovariectomized rats, which suggesting Ki20227 could also suppress TRAP-positive osteoclast-like cell development in a non-tumor-bearing rodent model[1].
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Ki20227 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
LEC injection-induced osteolysis model
Oral
40 mg/kg/day
Once daily for 2 weeks
To investigate the effect of Ki20227 on LEC-induced osteolysis, results showed that Ki20227 significantly reduced bone destruction.
J Bone Miner Res. 2017 May;32(5):939-950
Mouse
BAPN-induced thoracic aortic aneurysm and dissection model
Oral
30 mg/kg
Daily administration for 28 days
Suppression of macrophage accumulation in the aorta significantly decreased the incidence of TAAD and aortic rupture in mice.
Cell Discov. 2022 Feb 8;8(1):11
Mice
Global cerebral ischemia model induced by bilateral common carotid artery ligation (BCAL)
Intragastric administration
2 mg/kg/day
Once daily for 3 days
Ki20227 inhibition of CSF1R resulted in blockade of microglial proliferation and morphological changes, exacerbating neuronal degeneration and behavioral deficits.
Front Cell Neurosci. 2020 Oct 16;14:267
C57BL/6 mice
Ischemic stroke model
Oral gavage
0.002 mg/kg/day
Once daily for 7 or 14 days
Ki20227 pretreatment improved neurobehavioral function in stroke mice, upregulated synaptic protein expressions and dendritic spine density, while downregulating Iba1 expression, indicating inhibition of CSF1R signaling and activation of BDNF and autophagic pathways
Mediators Inflamm. 2020 Oct 31;2020:8796103
C57BL/6 male mice
Cerebral ischemia stroke model
Gavage
0.002 mg/kg/day
7 consecutive days, once daily
Ki20227 pretreatment significantly reduced neurological scores, improved neurological impairment, reduced brain infarction volume, inhibited microglia M1 phenotype and activated M2 phenotype, and inhibited NLRP3 inflammasome and NLRP3 signaling pathway activation.
Neural Plast. 2020 Aug 28;2020:8825954
Mice
Spontaneous melanoma model
Oral
30–40 mg/kg/day
Daily administration for 4 to 6 weeks
Postoperative use of Ki20227 significantly reduced tumor recurrence and inhibited metastatic growth
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