Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models

Bioorg Med Chem Lett. 2019 Jan 1;29(1):115-118. doi: 10.1016/j.bmcl.2018.10.051. Epub 2018 Nov 1.

Abstract

We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.

Keywords: Azetidine scaffold; CSF-1R; DFG-out; Type II inhibitor; cFMS.

MeSH terms

  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Structure-Activity Relationship

Substances

  • Azetidines
  • CSF1R protein, human
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • azetidine