Development Of Peptide Inhibitors Of ErbB Recepto Family As Potential Anti-cancer Drugs

The ErbB receptors comprise a family of receptor tyrosine kinases (ErbB 1-4), which activates intracellular signals through ligand-induced receptor dimerization. It has been found that the ErbB receptor family plays central roles in a variety of human cancers, and the ErbB receptors are overexpressed in many malignant tumours such as breast cancer and non-small cell lung cancer. Therefore, the study of finding inhibitors to the ErbB receptors becomes attractive to anti-cancer targets, and several monoclonal anti-ErbB receptor antibodies and ErbB receptor tyrosine kinase inhibitors are in use as or in clinical trials as anti-cancer drugs. Recent insight into the structures of the ErbB receptors has opened new opportunities for targeting specific aspects of ErbB receptor functions such as ligand-binding and homo- and heterodimerization.In this study, we have designed six amino peptides (termed B1-4DL and B3dln/B3dlc) with the aim of developing peptide inhibitors of one or several of the ErbB receptors. The effects of these peptides on the ErbB receptor functions were evaluated and characterized in vitro and in vivo.Using the surface plasmon resonance binding analysis, we have determined the binding profile of the three out of the four peptides against all the four members of the ErbB receptor family. We showed that each of the tested peptides binds two or four members of the ErbB receptor family, and thus have the potential of inhibiting different ErbB receptors concomitantly. Furthermore, we showed that one of the peptides, the B3DL peptide, inhibits ligand-induced ErbB1 phosphorylation and ligand-induced cell proliferation and also causes motility in L929 flbroblasts. The B3DL showed no effect on the human breast cancer cell line MCF-7, which expresses only the ErbB 2-4, but not the ErbB1. Although the third peptide, the B2DL peptide, had no effect on ErbBl phosphorylation, it inhibited the ligand-induced proliferation of L929 fibroblasts as well as MCF-7 cells, with the potential machnism of inhibition of ErbB2 function in these cells.In conclusion, our data so far suggested that the B2DL and the B3DL peptides have different impact on ErbB receptors: the B3DL peptide appears to be a selective inhibitor of ErbBl function, whereas the B2DL peptide may be a selective inhibitor of ErbB2 function. The use of small peptides to target ErbB receptor function in cancer cells provid new oppournities for targeted cancer therapy.