title: Novel Peptidomimetics for Inhibition of HER2:HER3 Heterodimerization in HER2-Positive Breast Cancer.
abstract: The current approach to treating HER2-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 HER2 domain IV with peptidomimetics and inhibit the protein-protein interactions (PPI) of HERs. Unlike antibodies, peptidomimetics have advantages in terms of stability, modification, and molecular size. We have designed peptidomimetics (compounds 5 and 9) that bind to HER2 domain IV, inhibit protein-protein interactions, and decrease cell viability in breast cancer cells with HER2 overexpression. We have shown, using enzyme fragment complementation and proximity ligation assays, that peptidomimetics inhibit the PPI of HER2:HER3. Compounds 5 and 9 suppressed the tumor growth in a xenograft mouse model. Furthermore, we have shown that these compounds inhibit PPI of HER2:HER3 and phosphorylation of HER2 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 HER2 protein and inhibit HER2:HER3 interaction, providing a novel method to treat HER2-positive cancer.
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Kanthala
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201.
authors.forename: Sashikanth
authors.initials: S
authors.lastname: Banappagari
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201.
authors.forename: Ameya
authors.initials: A
authors.lastname: Gokhale
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201.
authors.forename: Yong-Yu
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, LSU Health Sciences Center, Shreveport, LA 71103.
authors.forename: Gu
authors.initials: G
authors.lastname: Xin
authors.affiliation: Department of Pharmacology, LSU Health Sciences Center, Shreveport, LA 71103.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201.
authors.forename: Seetharama
authors.initials: S
authors.lastname: Jois
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D057786:Peptidomimetics / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D060066:Protein Interaction Maps / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D057786:Peptidomimetics; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3
keywords: HER2; HER3; breast cancer; peptidomimetic; protein-protein interaction