Structure-activity relationship, in vitro evaluation and in vivo anti-osteolytic effect of novel orally bioavailable c-Fms tyrosine kinase inhibitors Free

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Malignant tumors, especially in breast cancer and lung cancer, frequently metastasize to bone, and bone metastasis causes bone pain, bone fracture and hypercalcemia. The metastatic tumors promote osteolysis around them, and it is known that osteoclasts play a key role in the development of osteolysis in the bone metastatic lesions. M-CSF is considered as one of the most important factors for the differentiation of osteoclasts. Therefore, the inhibitor of M-CSF-dependent signaling through its receptor (c-Fms) is considered as a novel chemotherapeutic agent for osteolytic bone metastasis. We now report the development of orally bioavailable quinoline-urea derivatives with potent and selective inhibitory activity for c-Fms tyrosine kinase. Screening our compound library led to the discovery of potent inhibitors of c-Fms activity. As a result of the research involving the structure-activity relationships and optimizations for lead compounds, we found quinoline-ureas with an α-phenethyl group and with a 1-(2-thiazolyl)ethyl group that inhibited the c-Fms phophorylation with IC50 values in the low nanomolar range. The biochemical characterization of a representative compound, Ki20227, will be further described. The IC50 value of Ki20227 against c-Fms was determined to be 5 nM. Ki20227 exhibited a high level of activity for c-Fms compared with other tyrosine and serine/threonine kinases, for example, the IC50 values of VEGFR2, FGFR-2, c-Src, EGFR, PKCα and MAPK were 280 nM, >1000 nM, >1000 nM, >1000 nM, >1000 nM and >1000 nM, respectively. Ki20227 inhibited the development of osteoclast-like cells in a dose dependent manner. It also inhibited growth of the BAC1.2F5 mouse macrophage cell line with an IC50 value of 50 nM, but did not inhibit growth of the A375 human melanoma cells even at 1000 nM. These results strongly suggest that Ki20227 specifically affects the M-CSF signaling pathway. The oral administration of Ki20227 for 4 weeks at 40 mg/kg/day suppressed osteolytic bone metastasis in nude mice inoculated with A375 cells. Ki20227 would have applications in the treatment of osteolytic disease associated with bone metastasis and other bone diseases.