期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 11, 页码 5118-5123出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0915146107
关键词
peptide; cancer; EGFR; cetuximab; phage display
资金
- Department of Defense
- National Institutes of Health
- Gillson-Longenbaugh Foundation
- Marcus Foundation
- AngelWorks
- Susan G. Komen Breast Cancer Foundation
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 TGF alpha, 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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