title: Naamidine A is an antagonist of the epidermal growth factor receptor and an in vivo active antitumor agent.
abstract: The known 2-aminoimidazole alkaloid naamidine A (1) was isolated from a Fijian Leucetta sp. sponge as an inhibitor of the epidermal growth factor (EGF) receptor. The compound exhibited potent ability to inhibit the EGF signaling pathway and is more specific for the EGF-mediated mitogenic response than for the insulin-mediated mitogenic response. Evaluation in an A431 xenograft tumor model in athymic mice indicated that naamidine A exhibited at least 85% growth inhibition at the maximal tolerated dose of 25 mg/kg. Preliminary mechanism of action studies indicate that the alkaloid fails to inhibit the binding of EGF to the receptor and has no effect on the catalytic activity of purified c-src tyrosine kinase.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, and Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Copp
authors.forename: C R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: L
authors.initials: L
authors.lastname: Cornell
authors.forename: A M
authors.initials: AM
authors.lastname: Casazza
authors.forename: S
authors.initials: S
authors.lastname: Robinson
authors.forename: C M
authors.initials: CM
authors.lastname: Ireland
mesh_terms: D016475:3T3 Cells; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011161:Porifera / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D019061:src-Family Kinases
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C114816:naamidine A; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases