Colony Stimulating Factor-1 (also known as “m-CSF”) is a cytokine that regulates survival, proliferation and maturation of monocyte lineage cells, including macrophages and osteoclasts. The receptor for m-CSF (CSF1R), is a transmembrane protein expressed on the surface of these cells that contains an intracellular kinase domain (CSF1R kinase). Aberrant activity in these cell types is believed to augment metastatic activity in certain cancers, and drive inflammatory processes in a range of diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma.
Role of CSF1R in Oncology. In certain types of cancer, CSF1R is correlated with poorer survival and possibly metastatic disease. In addition, certain tumors secrete growth factors that promote osteoclast activity, which can result in hypercalcemia, increased risk of bone fracture, and bone pain. Research has shown that tumor-associated macrophages are involved in promoting tumor growth, metastasis, and angiogenesis. Since signaling through CSF1R is required for the maturation and survival of osteoclasts and macrophages, targeting CSF1R kinase represents a validated and attractive approach for treating and preventing malignancy-associated bone destruction and tumor metastatic behavior.
Role of CSF1R in Inflammatory Diseases. Macrophages produce a wide variety of cytokines, including those that promote inflammation such as TNF. Targeting CSF1R represents an attractive therapeutic approach for inflammatory diseases by modulating macrophage proliferation. In conditions such as rheumatoid arthritis, which involve bone and joint damage, targeting osteoclasts through CSF1R inhibition may assist in repairing joint damage and bone erosion associated with inflammatory processes.
CSF1R Program Development. Ambit has multiple chemical series of CSF1R inhibitors in preclinical development. These compounds have nanomolar affinity for the CSF1R kinase in both binding and cellular assays, and demonstrate activity in in vivo models of inflammation and tumor-mediated bone damage.