Open Access4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity.
Author(s) -
Elisabeth Buchdunger,
Uwe Trinks,
Helmut Mett,
Urs Regenass,
Marcel Müller,
Thomas Meyer,
Elaine McGlynn,
Lorenzo A. Pinna,
Peter Traxler,
Nicholas Lydon
Publication year - 1994
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.91.6.2334
Subject(s) - autophosphorylation , epidermal growth factor , tyrosine kinase , signal transduction , biology , receptor tyrosine kinase , platelet derived growth factor receptor , growth factor receptor , in vivo , a431 cells , growth factor receptor inhibitor , growth factor , epidermal growth factor receptor , cancer research , receptor , microbiology and biotechnology , biochemistry , kinase , protein kinase a , cell , oncogene , cell cycle
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.