In bone metastatic lesions, osteoclasts play a key role in the development of
osteolysis. Previous studies have shown that
macrophage colony-stimulating factor (
M-CSF) is important for the differentiation of osteoclasts. In this study, we investigated whether an inhibitor of
M-CSF receptor (c-Fms) suppresses osteoclast-dependent
osteolysis in bone metastatic lesions. We developed small molecule inhibitors against
ligand-dependent phosphorylation of c-Fms and examined the effects of these compounds on osteolytic bone destruction in a bone
metastasis model. We discovered a novel
quinoline-
urea derivative,
Ki20227 (N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-
thiazole-2-yl)ethyl]
urea), which is a c-Fms
tyrosine kinase inhibitor. The IC(50)s of
Ki20227 to inhibit c-Fms,
vascular endothelial growth factor receptor-2 (KDR),
stem cell factor receptor (c-Kit), and
platelet-derived growth factor receptor beta were found to be 2, 12, 451, and 217 nmol/L, respectively.
Ki20227 did not inhibit other
kinases tested, such as fms-like
tyrosine kinase-3,
epidermal growth factor receptor, or c-Src (c-src proto-oncogene product).
Ki20227 was also found to inhibit the
M-CSF-dependent growth of M-NFS-60 cells but not the
M-CSF-independent growth of A375 human
melanoma cells in vitro. Furthermore, in an osteoclast-like cell formation assay using mouse bone marrow cells,
Ki20227 inhibited the development of
tartrate-resistant acid phosphatase-positive osteoclast-like cells in a dose-dependent manner. In in vivo studies,
oral administration of
Ki20227 suppressed osteoclast-like cell accumulation and
bone resorption induced by metastatic
tumor cells in nude rats following intracardiac injection of A375 cells. Moreover,
Ki20227 decreased the number of
tartrate-resistant acid phosphatase-positive osteoclast-like cells on bone surfaces in ovariectomized (ovx) rats. These findings suggest that
Ki20227 inhibits osteolytic bone destruction through the suppression of
M-CSF-induced osteoclast accumulation in vivo. Therefore,
Ki20227 may be a useful therapeutic agent for osteolytic disease associated with bone
metastasis and other
bone diseases.