title: From combinatorial peptide selection to drug prototype (II): targeting the epidermal growth factor receptor pathway.
abstract: The epidermal growth factor receptor (EGFR), a tyrosine kinase, is central to human tumorigenesis. Typically, three classes of drugs inhibit tyrosine kinase pathways: blocking antibodies, small kinase inhibitors, and soluble ligand receptor traps/decoys. Only the first two types of EGFR-binding inhibitory drugs are clinically available; notably, no EGFR decoy has yet been developed. Here we identify small molecules mimicking EGFR and that functionally behave as soluble decoys for EGF and TGFalpha, ligands that would otherwise activate downstream signaling. After combinatorial library selection on EGFR ligands, a panel of binding peptides was narrowed by structure-function analysis. The most active motif was CVRAC (EGFR 283-287), which is necessary and sufficient for specific EGFR ligand binding. Finally, a synthetic retro-inverted derivative, (D)(CARVC), became our preclinical prototype of choice. This study reveals an EGFR-decoy drug candidate with translational potential.
authors.affiliation: David H Koch Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Giordano
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Bronk
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.forename: John
authors.initials: J
authors.lastname: Mendelsohn
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001665:Binding Sites; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D066246:ErbB Receptors; D000068818:Cetuximab