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

Kanthala, Shanthi; Singh, Sitanshu S.; Sable, Rushikesh; Pallerla, Sandeep; Jois, Seetharama D.

doi:10.18632/oncotarget.19013

Cited by 15 publications

(24 citation statements)

References 57 publications

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“…Structure-activity relationships of 18 ( Fig. 1) and analogs and their effect on HER2-positive breast cancer were described in our previous reports [20,30,[38][39][40][41][42].…”

Section: Design Of the Peptidomimetic Compound 18mentioning

confidence: 74%

“…To evaluate the significance, statistical analysis was performed by a one-tail T-test using Prism Graph Pad (GraphPad Software, San Diego). P< 0.05 was considered statistically significant [20,32].…”

Section: Western Blotmentioning

confidence: 99%

“…The crystal structure of human serum albumin (HSA) was obtained from the RCSB Protein Data Bank (PDB code: 2BXD). The structure of 18 was obtained from our previous work [20]. The binding of 18 to and HSA (PDB ID:2BXD) was modeled using AutoDock 4.0, and Lamarckian genetic algorithm (LGA) in Autodock was used to estimate the possible binding conformations of 18 with HSA [34].…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Compound 18 is highly specific for HER2 positive cancer cell lines [20]. A549 lung cancer cell lines overexpress HER2 protein and are used as in vivo and in vitro model of NSCLC.…”

Section: Compound 18 Inhibits Cellular Proliferation and Reduces The mentioning

confidence: 99%

“…S1). We have also evaluated the antiproliferative activity of 18 in different cell lines that overexpress HER2 or at basal level and in non-cancerous breast cell lines [20] (Supporting information Table S1). The selectivity of compound 18 is 200 times for HER2 positive cancer cell lines (SKBR-3, BT-474) as compared for non-cancerous cell line MCF-10A.…”

Section: Compound 18 Inhibits Cellular Proliferation and Reduces The mentioning

confidence: 99%

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In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

et al. 2020

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Studies related to lung cancer have shown a link between human epidermal growth factor receptor-2 (HER2) expression and poor prognosis in patients with non-small cell lung cancer (NSCLC). HER2 overexpression has been observed in 3-38% of NSCLC, while strong HER2 protein overexpression is found in 2.5% of NSCLC. However, HER2 dimerization is important in lung cancer, including EGFR mutated NSCLC. Since HER2 dimerization leads to cell proliferation, targeting the dimerization of HER2 will have a significant impact on cancer therapies. A peptidomimetic has been designed that can be used as a therapeutic agent for a subset of NSCLC patients overexpressing HER2 or possessing HER2 as well as EGFR mutation. A cyclic peptidomimetic (18) has been designed to inhibit protein-protein interactions of HER2 with its dimerization partners EGFR and HER3. Compound 18 exhibited antiproliferative activity in HER2-positive NSCLC cell lines at nanomolar concentrations. Western blot analysis showed that 18 inhibited phosphorylation of HER2 and Akt in vitro and in vivo. Stability studies of 18 at various temperature and pH (pH 1 and pH 7.6), and in the presence of liver microsomes indicated that 18 was stable against thermal and chemical degradation. Pharmacokinetic parameters were evaluated in nude mice by administrating single doses of 4 mg/kg and 6 mg/kg of 18 via IV. The anticancer activity of 18 was evaluated using an experimental metastasis lung cancer model in mice. Compound 18 suppressed the tumor growth in mice when compared to control. A proximity ligation assay further proved that 18 inhibits HER2:HER3 and EGFR: HER2 dimerization. Overall, these results suggest that 18 can be a potential treatment for HER2-dimerization related NSCLC.

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“…Structure-activity relationships of 18 ( Fig. 1) and analogs and their effect on HER2-positive breast cancer were described in our previous reports [20,30,[38][39][40][41][42].…”

Section: Design Of the Peptidomimetic Compound 18mentioning

confidence: 74%

Section: Western Blotmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

“…Compound 18 is highly specific for HER2 positive cancer cell lines [20]. A549 lung cancer cell lines overexpress HER2 protein and are used as in vivo and in vitro model of NSCLC.…”

Section: Compound 18 Inhibits Cellular Proliferation and Reduces The mentioning

confidence: 99%

Section: Compound 18 Inhibits Cellular Proliferation and Reduces The mentioning

confidence: 99%

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In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

et al. 2020

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Conformationally constrained cyclic grafted peptidomimetics targeting protein–protein interactions

Dahal,

Subramanian,

Shrestha

et al. 2023

Peptide Science

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Sunflower trypsin inhibitor‐1 (SFTI‐1) structure is used for designing‐grafted peptides as a possible therapeutic agent. The grafted peptide exhibits multiple conformations in solution due to the presence of proline in the structure of the peptide. To lock the grafted peptide into a major conformation in solution, a dibenzofuran moiety (DBF) was incorporated in the peptide backbone structure, replacing the Pro‐Pro sequence. NMR studies indicated a major conformation of the grafted peptide in solution. Detailed structural studies suggested that SFTI‐DBF adopts a twisted beta‐strand structure in solution. The surface plasmon resonance analysis showed that SFTI‐DBF binds to CD58 protein. A model for the protein‐SFTI‐DBF complex was proposed based on docking studies. These studies suggested that SFTI‐1 grafted peptide can be used to design stable peptides for therapeutic purposes by grafting organic functional groups and amino acids. However, when a similar strategy was used with another grafted peptide, the resulting peptide did not produce a single major conformation, and its biological activity was lost. Thus, conformational constraints depend on the sequence of amino acids used for SFTI‐1 grafting.

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Design of cyclic and d‐amino acids containing peptidomimetics for inhibition of protein‐protein interactions of HER2‐HER3

Pallerla

Naik

Singh

et al. 2018

Journal of Peptide Science

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HER2 receptors are surface proteins belonging to the epidermal growth factor family of receptors. Their numbers are elevated in breast, lung, and ovarian cancers. HER2-positive cancers are aggressive, have higher mortality rate, and have a poor prognosis. We have designed peptidomimetics that bind to HER2 and block the HER2-mediated dimerization of epidermal growth factor family of receptors. Among these, a symmetrical cyclic peptidomimetic (compound 18) exhibited antiproliferative activity in HER2-overexpressing lung cancer cell lines with IC values in the nanomolar concentration range. To improve the stability of the peptidomimetic, d-amino acids were introduced into the peptidomimetic, and several analogs of compound 18 were designed. Among the analogs of compound 18, compound 32, a cyclic, d-amino acid-containing peptidomimetic, was found to have an IC value in the nanomolar range in HER2-overexpressing cancer cell lines. The antiproliferative activity of compound 32 was also measured by using a 3D cell culture model that mimics the in vivo conditions. The binding of compound 32 to the HER2 protein was studied by surface plasmon resonance. In vitro stability studies indicated that compound 32 was stable in serum for 48 hours and intact peptide was detectable in vivo for 12 hours. Results from our studies indicated that 1 of the d-amino acid analogs of 18, compound 32, binds to the HER2 extracellular domain, inhibiting the phosphorylation of kinase of HER2.

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

Cited by 15 publications

References 57 publications

In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC

Conformationally constrained cyclic grafted peptidomimetics targeting protein–protein interactions

Design of cyclic and d‐amino acids containing peptidomimetics for inhibition of protein‐protein interactions of HER2‐HER3

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