Discovery of potent colony-stimulating factor 1 receptor inhibitors by replacement of hinge-binder moieties

Tumor-associated macrophages (TAMs) are predominantly associated with tumor growth. Colony-stimulating factor 1 receptor (CSF1R) acts as a key regulator of TAM survival and differentiation and is a molecular target for cancer therapies. Herein, novel CSF1R inhibitors were identified through a replacement strategy for the hinge-binding moiety. The introduction of imidazo[1,2-a]pyridine (49) or pyrazolo[1,5-a]pyridine (50) as hinge binders led to 87% and 82% inhibition at 10 nM for CSF1R in the enzymatic assay, with IC₅₀ values of 25 nM and 27 nM in MNFS60 cells, respectively. These derivatives significantly inhibited CSF1R phosphorylation in cells. Our approach could be utilized as a strategy to discover novel kinase inhibitors.