Design of novel lipidated peptidomimetic conjugates for targeting EGFR heterodimerization in HER2 + cancer

Abstract

The human epidermal growth factor receptor (EGFR) family is known to be involved in cell signaling pathways. The extracellular domain of EGFR consists of four domains, of which domain II and domain IV are known to be involved in the dimerization process. Overexpression of these receptors is known to play a significant role in heterodimerization of these receptors leading to the development of cancer. We have designed peptidomimetic molecules to inhibit the EGFR heterodimerization interaction that have shown antiproliferative activity and specificity for HER2-positive cancer cell lines. Among these, a peptidomimetic, compound 5, exhibited antiproliferative activity at low nanomolar concentrations in HER2-overexpressing cancer cell lines. To improve the stability of this peptidomimetic, we have designed and synthesized a novel conjugate of peptidomimetic compound 5 with a lipid, stearic acid. The antiproliferative activity of this conjugate was evaluated in HER2-positive cancer cell lines. Results suggested that the conjugate exhibited selective antiproliferative activity in HER2-overexpressing breast and lung cancer cell lines and was able to block HER2:HER3 heterodimerization. Also, the conjugate showed improved stability with a half-life of 5 h in human serum compared to the half-life of 2 h for parent compound 5. The binding affinity of the conjugate to HER2 protein was evaluated by SPR analysis, and the mode of binding of the lipid conjugate to domain IV of HER2 protein was demonstrated by docking analysis. Thus, this novel lipid conjugate can be used to target HER2-overexpressing cancers.

Lipidated Peptidomimetic Ligand-Functionalized HER2 Targeted Liposome as Nano-Carrier Designed for Doxorubicin Delivery in Cancer Therapy

“…Furthermore, free Dox showed lower cell viability ( Table 2 ). The results showed that the inclusion of SA-5 as a ligand also played a role in the anti-tumor effect of SA-5-Dox-LP formulation since SA-5 has antiproliferative activity as described in our earlier report [ 15 ]. Additionally, SA-5-Dox-LP showed lower cellular toxicity toward human lung fibroblast cells (HLFs), indicating the non-selective nature of ligand-functionalized liposome for non-cancerous cells that do not overexpress the HER2 protein.…”

“…Compound 5 and lipid conjugate of 5 (SA-5) were known to bind to the HER2 protein and inhibit EGFR dimerization in cancer cell lines [ 15 , 19 ]. SA-5 and SA-5-Dox-LP were evaluated for their ability to inhibit EGFR heterodimerization (protein-protein interactions) in vivo sample tissues of the lungs of mice treated with these formulations.…”

“…Here we describe the application of novel lipidized peptidomimetic conjugate SA-5 as a ligand ( Figure 1 ) for the preparation of liposomal chemotherapeutics targeted toward human epidermal growth factor receptor -2 (HER2) overexpressed cancer cells. In our previous study, we showed that SA-5 exhibited better selectivity for HER2 (EGFR) overexpressed cancer cells and indicated affinity to HER2 protein [ 15 ]. The objective of this work was to evaluate the potential of SA-5 as a ligand for HER2 overexpressing cancer targeting by liposomal chemotherapeutics carrier.…”

“…Our idea of the design for SA-5 was to use compound 5, which is known to bind to HER2 protein extracellular domain, as the ligand and conjugate stearic acid (SA) to it so that it can be incorporated into the liposome [ 15 , 16 ]. The ligand-incorporated liposome can be encapsulated with Dox or other chemotherapeutic agents to target the chemotherapeutic drug to HER2 protein that is overexpressed on cancer cells ( Figure 1 ).…”

Molecular Targeting of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR)

“…This conjugate accumulated in HER2-overexpressing cell lines and was observed to inhibit protein-protein interactions in vitro via a PLA assay. These peptidomimetics were also conjugated with fluorophores and doxorubicin to target the EGFR related cancer [ 161 , 162 ].…”