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.
- 15 March 1994
- journal article
- retracted article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 91 (6), 2334-2338
- https://doi.org/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-dianilinophthalimide selectively inhibited both ligand-induced EGF-R and pl85(c-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 p185(c-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.Keywords
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