4,5-bis(4-fluoroanilino)phthalimide: A selective inhibitor of the epidermal growth factor receptor signal transduction pathway with potent in vivo antitumor activity

• Published in: Clinical cancer research 1995-08, Vol.1 (8), p.813-821
• Main Authors: BUCHDUNGER, E, METT, H, LYDON, N. B, TRINKS, U, REGENASS, U, MÜLLER, M, MEYER, T, BEILSTEIN, P, WIRZ, B, SCHNEIDER, P, TRAXLER, P
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Biological and medical sciences; Biotransformation; Carcinoma, Squamous Cell - drug therapy; Cell Line, Transformed; Female; General aspects; Humans; Liver - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Pharmacology. Drug treatments; Phthalimides - pharmacokinetics; Phthalimides - therapeutic use; Phthalimides - toxicity; Rats; Rats, Inbred Strains; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - physiology; Signal Transduction - drug effects; Transplantation, Heterologous; Tumor Cells, Cultured; Urinary Bladder Neoplasms - drug therapy
• ISSN: 1078-0432; 1557-3265

Deregulated signal transduction via the epidermal growth factor (EGF) receptor family of tyrosine protein kinase growth factor receptors is associated with proliferative diseases such as cancer and psoriasis. In an attempt to selectively block signal transduction from the EGF receptor, we have synthesized a new class of dianilino-phthalimide tyrosine protein kinase inhibitors with selectivity for the EGF receptor tyrosine protein kinase. 4, 5-Dianilino-phthalimide (DAPH 1) was metabolized in vitro by mouse liver fractions and in vivo. The major metabolite has been identified as 4-(4-hydroxyanilino)-5-anilino-phthalimide. To specifically block this biotransformation (hydroxylation), we have synthesized 4,5-bis(4-fluoroanilino)phthalimide (DAPH 2), a potent and selective EGF receptor tyrosine protein kinase inhibitor. DAPH 2 inhibits the EGF receptor and protein kinase C beta2 enzymes with equal potency. In cells, DAPH 2 inhibits signal output from the EGF receptor, but not from other classes of receptor protein tyrosine kinases, such as the platelet-derived growth factor receptor, fibroblast growth factor receptor, insulin-like growth factor I receptor, and insulin receptor. Selective antitumor activity was demonstrated in vivo at well-tolerated doses in mice. This publication describes the biological profile of DAPH 2 and investigates its cellular and in vivo mechanism of action.