Oncotarget

Research Papers:

A peptidomimetic with a chiral switch is an inhibitor of epidermal growth factor receptor heterodimerization

Shanthi P. Kanthala, Yong-Yu Liu, Sitanshu Singh, Rushikesh Sable, Sandeep Pallerla and Seetharama D. Jois _

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Oncotarget. 2017; 8:74244-74262. https://doi.org/10.18632/oncotarget.19013

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Abstract

Shanthi P. Kanthala1, Yong-Yu Liu1, Sitanshu Singh1, Rushikesh Sable1, Sandeep Pallerla1 and Seetharama D. Jois1

1Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, USA

Correspondence to:

Seetharama D. Jois, email: jois@ulm.edu

Keywords: HER2, protein-protein interaction, breast cancer, peptidomimetic, dual inhibitor

Received: February 15, 2017     Accepted: June 16, 2017     Published: July 05, 2017

ABSTRACT

Among different types of EGFR dimers, EGFR-HER2 and HER2-HER3 are well known in different types of cancers. Targeting dimerization of EGFR will have a significant impact on cancer therapies. A symmetric peptidomimetic was designed to inhibit the protein-protein interaction of EGFR. The peptidomimetic (Cyclo(1,10)PpR (R) Anapa-FDDF-(R)-Anapa)R, compound 18) was shown to exhibit antiproliferative activity with an IC50 of 194 nM in HER2-expressing breast cancer cell lines and 18 nM in lung cancer cell lines. The peptidomimetic has a Pro-Pro sequence in the structure to stabilize the β-turn and a β-amino acid, amino napthyl propionic acid. To investigate the effect of the chirality of β-amino acid on the structure of the peptide and its antiproliferative activity, diastereoisomers of compound 18 were designed and synthesized. Structure-activity relationships of these compounds indicated that there is a chiral switch at β-amino acid in the designed compound. The peptidomimetic with R configuration at β-amino acid and with a L-Pro-D-Pro sequence was the most active compound (18). Using enzyme complement fragmentation assay and proximity ligation assay, we show that compound 18 inhibits HER2:HER3 and EGFR:HER2 dimerization. Surface plasmon resonance studies suggested that compound 18 binds to the HER2 extracellular domain and in particular to domain IV. The anticancer activity of compound 18 was evaluated using a xenograft model of breast cancer in mice; compound 18 suppressed the tumor growth in mice compared to control. Compound 18 was also shown to have a synergistic effect with erlotinib on EGFR mutated lung cancer cell lines.


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