From combinatorial peptide selection to drug prototype (II): Targeting the epidermal growth factor receptor pathway |
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| Authors: | Marina Cardó-Vila Ricardo J Giordano Richard L Sidman Lawrence F Bronk Zhen Fan John Mendelsohn Wadih Arap Renata Pasqualini |
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| Affiliation: | aDavid H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; ;bHarvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215; and ;cCenter for Targeted Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030 |
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| 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. |
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| Keywords: | peptide cancer EGFR cetuximab phage display |
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