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A potent protein‐tyrosine kinase inhibitor which selectively blocks proliferation of epidermal growth factor receptor‐expressing tumor cells in vitro and in vivo
Author(s) -
Lydon Nicholas B.,
Mett Helmut,
Mueller Marcel,
Becker Michael,
Cozens Robert M.,
Stover David,
Daniels Daren,
Traxler Peter,
Buchdunger Elisabeth
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980330)76:1<154::aid-ijc24>3.0.co;2-b
Subject(s) - in vivo , in vitro , tyrosine kinase , receptor tyrosine kinase , epidermal growth factor receptor , receptor protein tyrosine kinases , cancer research , epidermal growth factor , platelet derived growth factor receptor , microbiology and biotechnology , tyrosine kinase inhibitor , receptor , chemistry , biology , growth factor , kinase , biochemistry , cancer , genetics
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., ED 50 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. Int. J. Cancer 76:154–163, 1998.© 1998 Wiley‐Liss, Inc.