From combinatorial peptide selection to drug prototype (II): Targeting the epidermal growth factor receptor pathway

Marina Cardó-Vila, Ricardo J. Giordano, Richard L. Sidman, Lawrence F. Bronk, Zhen Fan, John Mendelsohn, Wadih Arap, Renata Pasqualini

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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 TGFα, 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.

Original languageEnglish (US)
Pages (from-to)5118-5123
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number11
DOIs
StatePublished - Mar 16 2010
Externally publishedYes

Keywords

  • Cancer
  • Cetuximab
  • EGFR
  • Peptide
  • Phage display

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'From combinatorial peptide selection to drug prototype (II): Targeting the epidermal growth factor receptor pathway'. Together they form a unique fingerprint.

Cite this