A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models

Authors

Sitanshu S. Singh, School of Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
George Mattheolabakis, School of Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
Xin Gu, Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71103, USA.
Sita Withers, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
Achyut Dahal, School of Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA.
Seetharama Jois, School of Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, 71201, USA. Electronic address: jois@ulm.edu.

Document Type

Article

Publication Date

4-15-2021

Abstract

Among the lung cancers, approximately 85% are histologically classified as non-small-cell lung cancer (NSCLC), a leading cause of cancer deaths worldwide. Epidermal growth factor receptors (EGFRs) are known to play a crucial role in lung cancer. HER2 overexpression is detected by immunohistochemistry in 2.4%-38% of NSCLC samples. EGFRs have been targeted with three generations of tyrosine kinase inhibitors (TKIs), and drug resistance has become a major issue; HER2 dimerization with EGFR also plays a major role in the development of resistance to TKI therapy. We have designed grafted peptides to bind to the HER2 extracellular domain (ECD) and inhibit protein-protein interactions of EGFR:HER2 and HER2:HER3. A sunflower trypsin inhibitor (SFTI-1) template was used to graft a peptidomimetic compound. Among several grafted peptides, SFTI-G5 exhibited antiproliferative activity in HER2-positive NSCLC cell lines such as Calu-3 cells with an IC value of 0.073 μM. SFTI-G5 was shown to bind to ECD of HER2 and inhibit EGFR:HER2 and HER2:HER3 dimerization and inhibit the phosphorylation of HER2 and downstream signaling proteins. As a proof-of-concept, the in vivo activity of SFTI-G5 was evaluated in two NSCLC mouse models. SFTI-G5 was able to inhibit tumor growth in both models. Furthermore, SFTI-G5 was shown to inhibit EGFR dimerization in tissue samples obtained from in vivo models. These grafted peptides can be used as novel dual inhibitors of EGFR dimerization in NSCLC.

Publication Source (Journal or Book title)

European journal of medicinal chemistry

First Page

113312

Recommended Citation

Singh, S. S., Mattheolabakis, G., Gu, X., Withers, S., Dahal, A., & Jois, S. (2021). A grafted peptidomimetic for EGFR heterodimerization inhibition: Implications in NSCLC models. European journal of medicinal chemistry, 216, 113312. https://doi.org/10.1016/j.ejmech.2021.113312