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26.09.2019 | Original Article

Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines

verfasst von: Hiba Zalloum, Tuka AbuThiab, Tareq Hameduh, Sara AlBayyari, Waleed Zalloum, Basha’er Abu-Irmaileh, Mohammad S. Mubarak, Malek Zihlif

Erschienen in: Breast Cancer | Ausgabe 2/2020

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Abstract

Background

Breast cancer is one of the most lethal types of cancer in women worldwide. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Previously, we have used quantitative structure activity relationship QSAR equations and their associated pharmacophore models to screen for new promising HER2 structurally diverse inhibitory leads which were tested against HER2-overexpressing SKOV3 ovarian cancer cell line.

Objective

In this study, we sought to explore the effect of most active ligands against different normal and breast cancer cell lines that represent different breast cancer subtypes with distinguished expression levels in HER2 and HER1.

Methods

We have tested the promising compounds against SKBR3, MDA-MB-231, MCF7, human fibroblast, and MCF10 cell lines. To understand the inhibitory effects of the active ligands against HER2 over expressed breast cancer cell lines, all inhibitors and the control compound, lapatinib, were docked into the active site of HER2 enzyme performed using Ligand Fit docking engine and PMF scoring function.

Results

Five ligands exhibited promising results with relatively low IC₅₀ values on cells that amplify HER2 and high IC₅₀ on those that do not express such a receptor. The most potent compound (compound 13) showed an IC₅₀ of 0.046 µM. To test their toxicity against normal cells, the active compounds were tested against both normal fibroblast and normal breast cancer cell MCF-10 and relatively high IC₅₀ values were scored. The IC₅₀ values on HER2 over-expressed breast cancer and normal fibroblast cells provided a promising safety index. Docking results showed the highest similarity in the binding site between the most active ligand and the lapatinib.

Conclusion

Our pharmacophore model resulted in a high potent ligand that shows high potency against HER2 positive breast cancer and relatively low toxicity towards the normal human cells.

Graphic abstract

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Titel: Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines
verfasst von: Hiba Zalloum
Tuka AbuThiab
Tareq Hameduh
Sara AlBayyari
Waleed Zalloum
Basha’er Abu-Irmaileh
Mohammad S. Mubarak
Malek Zihlif
Publikationsdatum: 26.09.2019
Verlag: Springer Japan
Erschienen in: Breast Cancer / Ausgabe 2/2020
Print ISSN: 1340-6868
Elektronische ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-019-01011-z

Springer Medizin

Comparative anti-proliferative effects of potential HER2 inhibitors on a panel of breast cancer cell lines