title: Inhibiting epidermal growth factor receptor at a distance.
abstract: The epidermal growth factor receptor (EGFR) tyrosine kinase is implicated in a large number of human cancers. Most EGFR inhibitors target the extracellular, growth factor-binding domain or the intracellular, ATP-binding domain. Here we describe molecules that inhibit the kinase activity of EGFR in a new way, by competing with formation of an essential intradimer coiled coil containing the juxtamembrane segment from each member of the receptor partnership. The most potent molecules we describe bind EGFR directly, decrease the proliferation of wild-type and mutant EGFR-dependent cells lines, inhibit phosphorylation of EGFR and downstream targets, and block coiled coil formation as judged by bipartite tetracysteine display. Potency is directly correlated with the ability to block coiled coil formation within full-length EGFR in cells.
authors: Department of Chemistry and ‡Department of Molecular, Cellular and Developmental Biology, Yale University , New Haven, Connecticut 06520-8107, United States.
authors: Julie K-L
authors: JK
authors: Sinclair
authors: Elizabeth V
authors: EV
authors: Denton
authors: Alanna
authors: A
authors: Schepartz
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000495:Allosteric Site; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003412:Cricetulus; D003545:Cysteine / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D006838:Hydrocarbons; D007211:Indoles; D010455:Peptides; D011719:Pyrazines; C014730:oxyluciferin; D000255:Adenosine Triphosphate; D066246:ErbB Receptors; D003545:Cysteine