Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment

Eur J Med Chem. 2017 Aug 18;136:372-381. doi: 10.1016/j.ejmech.2017.05.006. Epub 2017 May 11.


Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells. The representative compound 13b showed nM IC50 values against K562 and A549 cells, and inhibited EGFR at inhibition rate of 33.53% at 10 μM and Src at inhibition rate of 72.12% at 1 μM. Furthermore, compound 13b could inhibit the expression of EGFR, p-EGFR, Src and p-Src. Moreover, 13b efficiently inhibited the invasion of tumor cells and induced cancer cells apoptosis. Our study suggested that azaacridine scaffold can be developed as novel multi-target kinase inhibitors for cancer therapy.

Keywords: Antitumor; Apoptosis; Azaacridine derivatives; EGFR; Invasion; Src.

MeSH terms

  • Acridines / chemical synthesis
  • Acridines / chemistry
  • Acridines / pharmacology*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism


  • Acridines
  • Antineoplastic Agents
  • Aza Compounds
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors
  • src-Family Kinases