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. 1994 Mar 15;91(6):2334-8.
doi: 10.1073/pnas.91.6.2334.

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

E Buchdunger  1 , U Trinks, H Mett, U Regenass, M Müller, T Meyer, E McGlynn, L A Pinna, P Traxler, N B Lydon
Affiliations

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

E Buchdunger et al. Proc Natl Acad Sci U S A. .

Retraction in

  • Retractions.
    Buchdunger E, Trinks U, Mett H, Regenass U, Meyer T, McGlynn E, Pinna LA, Traxler P, Lydon NB, Zimmermann J. Buchdunger E, et al. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12069. doi: 10.1073/pnas.95.20.12069-a. Proc Natl Acad Sci U S A. 1998. PMID: 9786782 Free PMC article. No abstract available.

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.

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