Novel Peptidomimetics for Inhibition of HER 2: HER 3 Heterodimerization in HER 2‐Positive Breast Cancer

The current approach to treating HER 2‐overexpressed breast cancer is the use of monoclonal antibodies or a combination of antibodies with traditional chemotherapeutic agents or kinase inhibitors. Our approach is to target clinically validated HER 2 domain IV with peptidomimetics and inhibit the protein–protein interactions ( PPI ) of HER s. Unlike antibodies, peptidomimetics have advantages in terms of stability, modification, and molecular size. We have designed peptidomimetics (compounds 5 and 9 ) that bind to HER 2 domain IV , inhibit protein–protein interactions, and decrease cell viability in breast cancer cells with HER 2 overexpression. We have shown, using enzyme fragment complementation and proximity ligation assays, that peptidomimetics inhibit the PPI of HER 2: HER 3. Compounds 5 and 9 suppressed the tumor growth in a xenograft mouse model. Furthermore, we have shown that these compounds inhibit PPI of HER 2: HER 3 and phosphorylation of HER 2 as compared to control in tissue samples derived from in vivo studies. The stability of the compounds was also investigated in mouse serum, and the compounds exhibited stability with a half‐life of up to 3 h. These results suggest that the novel peptidomimetics we have developed target the extracellular domain of HER 2 protein and inhibit HER 2: HER 3 interaction, providing a novel method to treat HER 2‐positive cancer.