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.
Kazutaka Ikegashira  1 ,  Taku Ikenogami  1 ,  Takayuki Yamasaki  1 ,  Yasunori Hase  1 ,  Takayuki Yamaguchi  1 ,  Koji Inagaki  1 ,  Satoki Doi  1 ,  Tsuyoshi Adachi  1 ,  Yoshihisa Koga  1 ,  Hiromasa Hashimoto  1
Affiliations
  • 1. Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
PMID: 30442420 DOI: 10.1016/j.bmcl.2018.10.051
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.
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