Novel peptidomimetics for inhibition of HER2:HER3 heterodimerization in HER2-positive breast cancer

Shanthi Kanthala, Sashikanth Banappagari, Ameya Gokhale, Yong Yu Liu, Gu Xin, Yunfeng Zhao, Seetharama Jois

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)702-714
Number of pages13
JournalChemical Biology and Drug Design
Volume85
Issue number6
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Keywords

  • HER2
  • HER3
  • breast cancer
  • peptidomimetic
  • protein-protein interaction

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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