Human
epidermal growth factor receptor-2 (HER2) is a
tyrosine kinase family
protein receptor that is known to undergo heterodimerization with other members of the family of
epidermal growth factor receptors (EGFR) for cell signaling. Overexpression of HER2 and deregulation of signaling has implications in breast, ovarian, and
lung cancers. We have designed several
peptidomimetics to block the HER2-mediated dimerization, resulting in antiproliferative activity for
cancer cells. In this work, we have investigated the structure-activity relationships of
peptidomimetic analogs of Compound 5. Compound 5 was conformationally constrained by N- and C-terminal modification and cyclization as well as by substitution with d-
amino acids at the N-and C-termini. Among the compounds studied in this work, a
peptidomimetic Compound 21 with d-amino acid substitution and its N- and C-termini capped with acetyl and
amide functional groups and a reversed sequence compared to that of Compound 5 exhibited better antiproliferative activity in HER2-overexpressed breast, ovarian, and
lung cancer cell lines.
Compound 21 was further evaluated for its
protein-
protein interaction (PPI) inhibition ability using
enzyme fragment complementation assay, proximity
ligation assay, and Western blot analysis. Results suggested that
Compound 21 is able to block HER2:HER3 interaction and inhibit phosphorylation of the
kinase domain of HER2. The mode of binding of
Compound 21 to HER2
protein was modeled using a docking method.
Compound 21 seems to bind to domain IV of HER2 near the PPI site of EGFR:HER2, and HER:HER3 and inhibit PPI.