4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity

Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2334-8. doi: 10.1073/pnas.91.6.2334.

Abstract

Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalmide selectively inhibited both ligand-induced EGF-R and p185c-erbB2 autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.

Publication types

  • Retracted Publication

MeSH terms

  • 3T3 Cells
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Division
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Molecular Conformation
  • Molecular Structure
  • Phosphorylation
  • Phthalimides / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Phthalimides
  • ErbB Receptors