TY - JOUR
T1 - From combinatorial peptide selection to drug prototype (II)
T2 - Targeting the epidermal growth factor receptor pathway
AU - Cardó-Vila, Marina
AU - Giordano, Ricardo J.
AU - Sidman, Richard L.
AU - Bronk, Lawrence F.
AU - Fan, Zhen
AU - Mendelsohn, John
AU - Arap, Wadih
AU - Pasqualini, Renata
PY - 2010/3/16
Y1 - 2010/3/16
N2 - 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.
AB - 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.
KW - Cancer
KW - Cetuximab
KW - EGFR
KW - Peptide
KW - Phage display
UR - http://www.scopus.com/inward/record.url?scp=77950419552&partnerID=8YFLogxK
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U2 - 10.1073/pnas.0915146107
DO - 10.1073/pnas.0915146107
M3 - Article
C2 - 20190183
AN - SCOPUS:77950419552
SN - 0027-8424
VL - 107
SP - 5118
EP - 5123
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -