PMID: 9533776Apr 9, 1998Paper

A potent protein-tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor-expressing tumor cells in vitro and in vivo

International Journal of Cancer. Journal International Du Cancer
N B LydonE Buchdunger

Abstract

A calculated 3-D model of the kinase domain of the epidermal growth factor receptor (EGF-R) protein-tyrosine kinase (PTK) was used to develop a pharmacophore model for ATP-competitive inhibitors and, subsequently, a new class of selective EGF-R kinase inhibitors. CGP 59326A, a highly selective and potent inhibitor of the EGF-R in vitro, inhibited the proliferation of EGF-R-expressing epithelial lines, while having little anti-proliferative activity against EGF-R-negative lines. In contrast to previously described inhibitors, CGP 59326A had potent and selective in vivo anti-tumor activity at well-tolerated doses against EGF-R-expressing tumors (e.g., ED50 of 0.78 to 1.5 mg/kg for inhibition of A431 tumor growth). CGP 59326A inhibited growth of human tumor xenografts expressing the EGF-R but showed little activity against EGF-R-negative xenografts. Combination of CGP 59326A with cytotoxic agents resulted in tumor regression and cures. The high selectivity and attractive biological profile of CGP 59326A suggest that it could have therapeutic value in the treatment of proliferative diseases which involve mitogenic signaling from the EGF-R.

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Citations

Mar 11, 2000·Journal of Receptor and Signal Transduction Research·A D EbertD S Salomon
Feb 14, 2002·British Journal of Haematology·Farhad RavandiZeev Estrov
Jun 19, 2003·Journal of the National Cancer Institute·Viktor Grünwald, Manuel Hidalgo
Jan 19, 2005·British Journal of Cancer·S-J ParkS-H Lee
Jun 28, 2001·Oncogene·J Mendelsohn, J Baselga
Dec 15, 2000·Oncogene·F A Al-Obeidi, K S Lam
May 5, 2001·Pharmacology & Therapeutics·C R Weinstein-OppenheimerJ A McCubrey
Aug 24, 1999·Pharmacology & Therapeutics·J R Woodburn
Mar 15, 2002·Seminars in Oncology·Carlos L ArteagaSaid Sebti
Dec 26, 2001·Chemical Reviews·A J Bridges

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