Synthesis of novel 1,2,4-triazine scaffold as FAK inhibitors with antitumor activity

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1727-1730. doi: 10.1016/j.bmcl.2017.02.072. Epub 2017 Feb 28.

Abstract

A series of 1,3,5-triazinic inhibitors of focal adhesion kinase (FAK) has recently been shown to exert antiangiogenic activity against HUVEC cells and anticancer efficacy against several cancer cell lines. In this report, we designed and synthesized a series of new compounds containing a 1,2,4-triazine core as novel scaffold for FAK inhibitors. These compounds displayed 10-7M IC50 values, and the best one showed IC50 value of 0.23μM against FAK enzymatic activity. Among them, several inhibitors potently inhibited the proliferation of glioblastoma (U-87MG) and colon (HCT-116) cancer cell lines. Docking of compound 10 into the active site of the FAK kinase was performed to explore its potential binding mode.

Keywords: 1,2,4-Triazines; Anti-cancer activity; FAK inhibitors; Molecular docking; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Triazines / chemistry*
  • Triazines / pharmacology*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Triazines
  • 1,2,4-triazine
  • Focal Adhesion Protein-Tyrosine Kinases