From combinatorial peptide selection to drug prototype (I): Targeting the vascular endothelial growth factor receptor pathway (original) (raw)

2010, Proceedings of the …

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. peptide | cancer | EGFR | cetuximab | phage display T he epidermal growth factor receptor (EGFR) is a member of the ErbB family of tyrosine kinase receptors (1, 2). Several lines of evidence indicate that the EGFR is abnormally activated in many types of epithelial tumors. The first therapeutic agent targeted to the EGFR is a monoclonal antibody, cetuximab, which blocks ligand binding and thus inhibits tyrosine kinase activity (3). In the past few years, it has become clear that specific somatic EGFR mutations present in non-small-cell lung cancer potentiate responses to certain low molecular weight tyrosine kinase inhibitors and monoclonal antibodies (1, 4-8); mutation of the K-ras gene also has been associated with survival in patients with advanced colon cancer treated with cetuximab (9). These agents, both antibodies and tyrosine kinase inhibitors, prevent ligand-induced receptor activation and downstream signaling and result in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis (10, 11).