Structure-based approaches to inhibition of erbB receptors with peptide mimetics.

The epidermal growth factor (EGF) family of tyrosine kinase receptors (erbB receptors) are expressed at high levels in a wide variety of human cancers and have been associated with various features of advanced disease and poor prognosis. Therapeutic blockade of erbB signaling is a novel approach to the treatment of human tumors that could offer a noncytotoxic alternative to cancer treatment. A number of monoclonal antibodies (MAbs) directed against erbB receptors have been developed and demonstrated promising therapeutic results. We have designed small-molecule peptide mimetics of an anti-erbB rhu MAb 4D5 that can mimic structural and functional properties of the parental antibody. An alternative structure-based strategy of erbB receptor blockade with peptide mimetics by targeting receptor dimerization interfaces is also described.