Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors

Bioorg Med Chem Lett. 2019 Jan 15;29(2):271-275. doi: 10.1016/j.bmcl.2018.11.037. Epub 2018 Nov 19.

Abstract

Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells.

Keywords: Anti- tumor activity; CSF-1R; Colony stimulating factor-1; FMS; Human breast adenocarcinoma cells; Tumor associated macrophages (TAMs).

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Ligands
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Ligands
  • Protein Kinase Inhibitors
  • Pyrimidines
  • thieno(2,3-d)pyrimidine
  • Receptor, Macrophage Colony-Stimulating Factor