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

Eur J Med Chem. 2021 Apr 15:216:113298. doi: 10.1016/j.ejmech.2021.113298. Epub 2021 Feb 22.

Abstract

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.

Keywords: CSF1R; Hinge binder; Kinase inhibitor.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design*
  • Humans
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • RAW 264.7 Cells
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Structure-Activity Relationship

Substances

  • CSF1R protein, human
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • pyrazolo(3,4-b)pyridine
  • imidazo(1,2-a)pyridine