Colony-stimulating factor-1 receptor inhibitors for the treatment of cancer and inflammatory disease.
FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is over-expressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as well as autoimmune and inflammatory disease, such as rheumatoid arthritis (RA). Numerous FMS inhibitors with structurally distinct chemotypes have been developed and exhibit potent in vitro activity, but only a limited number of compounds have progressed clinically due to poor selectivity. To date, only a handful of FMS inhibitors have been tested in models of metastatic bone disease and RA. This review will summarize the biology of FMS and its function in bone physiology, inflammation, immunity, and cancer. In addition, efforts directed towards identifying FMS-selective small molecule inhibitors as well as the advancement of non-selective inhibitors in the clinic will be highlighted. Furthermore, emerging monoclonal antibody-based therapeutic strategies specifically targeting M-CSF will be described.
Patel
Sharmila
S
Johnson & Johnson Pharmaceutical Research & Development LLC, Spring House, PA 19477, USA.
Player
Mark R
MR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001842:Bone and Bones / Q000502:physiology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D016184:Receptors, Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D016184:Receptors, Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor