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Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of...

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Autores principales: Balbuena-Rebolledo, Irving, Padilla-Martínez, Itzia Irene, Rosales-Hernández, Martha Cecilia, Bello, Martiniano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401258/
https://www.ncbi.nlm.nih.gov/pubmed/34451888
http://dx.doi.org/10.3390/ph14080791
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author Balbuena-Rebolledo, Irving
Padilla-Martínez, Itzia Irene
Rosales-Hernández, Martha Cecilia
Bello, Martiniano
author_facet Balbuena-Rebolledo, Irving
Padilla-Martínez, Itzia Irene
Rosales-Hernández, Martha Cecilia
Bello, Martiniano
author_sort Balbuena-Rebolledo, Irving
collection PubMed
description Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.
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spelling pubmed-84012582021-08-29 Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2 Balbuena-Rebolledo, Irving Padilla-Martínez, Itzia Irene Rosales-Hernández, Martha Cecilia Bello, Martiniano Pharmaceuticals (Basel) Article Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR. MDPI 2021-08-12 /pmc/articles/PMC8401258/ /pubmed/34451888 http://dx.doi.org/10.3390/ph14080791 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Balbuena-Rebolledo, Irving
Padilla-Martínez, Itzia Irene
Rosales-Hernández, Martha Cecilia
Bello, Martiniano
Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title_full Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title_fullStr Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title_full_unstemmed Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title_short Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2
title_sort repurposing fda drug compounds against breast cancer by targeting egfr/her2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401258/
https://www.ncbi.nlm.nih.gov/pubmed/34451888
http://dx.doi.org/10.3390/ph14080791
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