Discovery of 2,4-diarylaminopyrimidine derivatives bearing dithiocarbamate moiety as novel FAK inhibitors with antitumor and anti-angiogenesis activities

Eur J Med Chem. 2019 Sep 1:177:32-46. doi: 10.1016/j.ejmech.2019.05.048. Epub 2019 May 18.

Abstract

A series of 2,4-diarylaminopyrimidine derivatives containing dithiocarbamate moiety were designed by molecular hybridization strategy and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most of these compounds exhibit significant antiproliferative activities on human cancer cell lines expressing high levels of FAK at nanomolar concentrations. The compound 14z was identified as the most potent FAK inhibitor among these candidates. 14z has excellent anti-proliferative effect with IC50 values from 0.001 μM to 0.06 μM on HCT116, PC-3, U87-MG and MCF-7 cell lines and relatively less cytotoxicity to a nonmalignant cell line MCF-10A compared with MCF-7 cells (SI value > 10). 14z also exhibits significant FAK inhibitory activity (IC50 = 0.07 nM). In addition, compound 14z causes cell cycle arrest at G2/M and prompted apoptosis in both HCT116 and MCF-7 cells in a dose-dependent manner. Further studies show that compound 14z inhibits migration of MCF-7 and has anti-angiogenesis effect on HUVEC cells.

Keywords: 2,4-Diarylaminopyrimidine; Anti-angiogenesis; Anti-tumor activity; Dithiocarbamate; FAK inhibitors.

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Angiogenesis Inhibitors / toxicity
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Focal Adhesion Kinase 1 / antagonists & inhibitors*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / toxicity
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Pyrimidines / toxicity
  • Structure-Activity Relationship
  • Thiocarbamates / chemical synthesis
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology*
  • Thiocarbamates / toxicity

Substances

  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiocarbamates
  • Focal Adhesion Kinase 1
  • PTK2 protein, human