Clinical Cancer Research, Vol 1, Issue 8 813-821, Copyright © 1995 by American Association for Cancer Research

ARTICLES

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

E Buchdunger, H Mett, U Trinks, U Regenass, M Muller, T Meyer, P Beilstein, B Wirz, P Schneider and P Traxler
Pharmaceuticals Division, Oncology Research and Preclinical Safety Departments, Ciba-Geigy Limited, CH-4002 Basel, Switzerland.

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.

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