title: 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.
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.
authors.affiliation: CIBA Pharmaceuticals Division, CIBA-Geigy Limited, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Buchdunger
authors.forename: U
authors.initials: U
authors.lastname: Trinks
authors.forename: H
authors.initials: H
authors.lastname: Mett
authors.forename: U
authors.initials: U
authors.lastname: Regenass
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: E
authors.initials: E
authors.lastname: McGlynn
authors.forename: L A
authors.initials: LA
authors.lastname: Pinna
authors.forename: P
authors.initials: P
authors.lastname: Traxler
authors.forename: N B
authors.initials: NB
authors.lastname: Lydon
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D015394:Molecular Structure; D010766:Phosphorylation; D010797:Phthalimides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010797:Phthalimides; D066246:ErbB Receptors